System and methods for treating cancer cells with alternating polarity magnetic fields

ABSTRACT

Systems and method for destroying or inhibiting cancer cells and other rapidly-dividing cells include applying AP magnetic fields having a defined frequency of 5 Hz-500 kHz and a field strength of 0.1-5000 μT to a target body area that includes the cancer or other rapidly-dividing cells, and modifying the cancer or tumor microenvironment to increase the presence of cancer-suppressive cells or decrease the presence of cancer-promoting cells. In various embodiments, the systems and methods may include adjusting the therapy based on the dosage of an immunotherapy drug administered to the patient before, during, or after the application of the AP magnetic fields.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.17/396,608, filed Aug. 6, 2021, which is a Continuation-In-Part of U.S.patent application Ser. No. 17/308,019, filed May 4, 2021 and entitled“System and Methods for Treating Cancer Cells With Alternating PolarityMagnetic Fields,” which is a Continuation of U.S. patent applicationSer. No. 16/784,239, filed Feb. 6, 2020, now U.S. Pat. No. 11,027,143which claims the benefit of priority to U.S. Provisional Application No.62/802,685, filed Feb. 7, 2019. U.S. patent application Ser. No.17/396,608, filed Aug. 6, 2021 also claims priority to U.S. ProvisionalApplication Ser. No. 63/127,129, filed Dec. 17, 2020, U.S. ProvisionalApplication No. 63/063,198, filed Aug. 7, 2020, and U.S. ProvisionalApplication Ser. No. 62/802,685 filed Feb. 7, 2019. Each of theforegoing applications is hereby incorporated herein by reference in itsentirety.

TECHNICAL FIELD

The present invention involves treating rapidly proliferating ordividing cells, such as cancer cells, and more specifically to systemsand methods for selectively inhibiting or destroying rapidly dividingcells by applying an alternating magnetic field having definedcharacteristics to a target area of a patient's body. Some embodimentsof the invention provide a wearable system capable of providing anambulatory therapy to a non-stationary patient by applying a magneticfield to inhibit or destroy rapidly dividing cells to the target bodyarea.

BACKGROUND OF THE INVENTION

Cell division is a reproductive process in all living systems, includingwithout limitation simple one-celled organisms such as bacteria andprotozoa, as well as more complex organisms such as algae, plants, andanimals, including humans. The cell division cycle involves a series ofevents within the cell that leads to a duplication of the DNA of thecell, with one of the duplicate DNA sequences going to each of twodaughter cells. Prokaryotic cells are one-celled organisms that lack anenclosed nucleus and reproduce by a cell division process known asfission. More complex organisms with enclosed nuclei are calledeukaryotes, whose cells asexually reproduce by a three-part celldivision process involving periods known as interphase, mitosis, andcytokinesis. In the reproduction of sexual cells (i.e., egg and sperm)of more complex organisms, mitosis is replaced by meiosis.

During interphase, the parent cell produces nutrients and othercomponents necessary for mitosis, and the DNA is duplicated as looselypacked chromatin. Mitosis involves separation of the duplicated DNA inthe nucleus of the eukaryotic cell into two nuclei, each having acomplete copy of the duplicated DNA. In cytokinesis, the cytoplasm,organelles & cell membrane are divided, forming two daughter cells ofroughly equal size.

The process of mitosis is further divided into the stages of prophase,prometaphase, metaphase, anaphase, and telophase. In prophase, the DNAduplicated during interphase condenses into discrete long, thinchromosomes having two chromatids joined by a centromere. Each cell hastwo centrioles, which move to opposite poles of the cell duringprophase. Microtubules radiate from near the two centrioles toward thecenter of the cell, including some which extend to the chromatids andhelp to separate the two chromatids into separate daughter chromatids.In metaphase, the chromosomes move toward the cell equator and align inthe metaphase plane (or equatorial plane). The daughter chromatidsseparate from each other at the equator during early anaphase by movingalong the microtubule spindle fibers toward the centromeres at oppositepoles of the cell, a process which elongates the cell. In late anaphasethe daughter chromosomes each reach their opposite poles of the cell,and the cell membrane begins to pinch to form the two daughter cells,which is part of cytokinesis, or the process by which the daughter cellsare separated. During telophase, the microtubules continue to lengthenand a new nuclear envelope forms around each of the separated daughterchromosomes, each of which has an identical set of chromosomes, andcytokinesis proceeds with further pinching of the two daughter cellstoward becoming separate entities. By the end of telophase, themicrotubule spindles disappear. Finally, the daughter cells fullyseparate, completing cytokinesis.

Cancer cells and some non-cancerous cells (e.g., non-malignant tumors)proliferate or grow in an uncontrolled manner in contrast to normalcells. In addition to the extra space such tumors or cells occupy, theymay also damage nearby normal cells. Cancer cells may also metastasize,traveling to other locations in the body, where they continue tohyperproliferate and may form new tumors. The rapid growth of tumors andcancer cells results from their rapid rate of cell division compared tonormal cells.

Many effective anti-cancer and anti-tumor therapies are based on thefact that cells in the process of dividing are more sensitive toradiation and many drugs than non-dividing cells. Because tumor cellsdivide much more frequently than normal cells, it is possible, by usingtherapies that act on tumor cells while they are dividing, toselectively damage or destroy them while leaving normal cells—whichdivide less frequently—less affected. However, because many types ofcancer cells are only slightly more susceptible to radiation and/orchemotherapy agents than normal cells, it is not always possible toselectively affect tumor cells while leaving normal cells unaffected.Consequently, many radiation and chemotherapy agents significantlydamage normal cells as well as tumor cells, leading to a significantpatient burden (e.g., pain, scarring, organ damage, blood damage,impaired immune system function, etc.) for even “successful” treatments.

In addition to radiation and chemotherapeutic agents, other therapiesinvolving different modes of action have been used to treat tumor cells,including without limitation ultrasonic and electrical therapies.Electrical currents and electrical fields have been used for decades formedical purposes.

One type of electrical therapy involves applying an electrical currentthrough body tissue separated by two or more conductive electrodes. Thistype of therapy may be used, for example to stimulate or excite muscleor nerve tissue (e.g., pacemakers, defibrillators, neurostimulators) orto generate heat within a desired body tissue (e.g., thermal therapiesto remodel collagen or to ablate tissue). Electrical therapies involvingconductive electrodes may involve direct current or alternating currentat a wide range of frequencies (e.g., less than 1 Hz to above 1 MHz).The energy from electrical currents is delivered to tissue based on theelectrical conductive characteristics (e.g., resistance, capacitance) ofthe tissue. Since these properties are similar for both tumor and normalcells, such therapies affect both tumor and normal cells (e.g.,destroying both by heat if they are within the current path) in the samemanner. At lower frequencies (typically below 20 kHz), the use ofconductive electrodes may be used to stimulate muscle or nerve tissue toactivate muscle or nerve fibers. At frequencies used in many electricaltherapies (e.g., tens of kHz to MHz), stimulation with conductiveelectrodes is too rapid for stimulation signals to propagate throughsuch tissue and the signals are “shorted.”

Another medical use of electrical energy involves the use of insulatedelectrodes to deliver high frequency electrical energy radiatively orinductively to target tissue. For example, radio frequency (RF) ormicrowave energy may be applied radiatively to tissue through the air oranother electrically insulating material separating the electrodes fromthe tissue being treated. The effect of this type of electrical energyon living tissue is based on the dielectric properties of the tissuerather than their conductive characteristics.

More recently, insulated electrodes have been used to treat cancer cellsand other rapidly proliferating cells by applying AC electric fields atfrequencies of 50-500 kHz and electric field strengths of about 10-1000V/m to a target body area that includes such cells. Such therapy isoften referred to as TC (“tumor curing”) field or TTF (“tumor treatmentfield”) therapy. In U.S. Pat. No. 6,868,289, which is herebyincorporated by reference in its entirety, a method and apparatus aredisclosed for destroying rapidly proliferating cells using insulatedelectrodes to generate an electric field. At electric field frequenciesof 50-500 kHz, the cell membranes of the dividing cells act toconcentrate the electric field lines at the cleavage furrow separatingthe two daughter cells of the dividing cell. The high-density field atthe cleavage furrow causes polarized or charged intracellular componentswithin the cell to move toward the high-density field lines at thecleavage furrow, eventually disrupting the cell membrane at the cleavagefurrow, and destroying the diving daughter cells.

In U.S. Pat. No. 8,019,414, which is hereby incorporated by reference inits entirety, a method of killing or destroying cancer cells isdisclosed that involves applying an electric field together with anothercancer therapy such as radiation or chemotherapy drugs. The electricalfield may be a field such as that disclosed in the '289 patent.

The use of electric fields to destroy cancer cells, while effective atcertain frequencies and electrical field strengths, is limited in manypractical respects. To provide a safe and consistent electrical fieldstrength, the electrodes of systems such as those disclosed in the '298and '414 patents must be in intimate contact with the tissue (e.g.,skin) of the patient at all times during the treatment. To ensure goodcontact with the patient's skin, it may be necessary to shave all hairfrom the skin to which the electrodes are coupled. Because the therapymay be delivered for an extended period of time, the electrodesfrequently cause skin irritation at the electrode contact site. Forexample, in one recent study of TTF therapy, forty-three percent (43%)of patients experienced some skin irritation, with 1% reporting severeskin irritation. The relatively high incidence of skin irritation orpain may prohibit the therapy in sensitive body areas (e.g., breasttissue, etc.). TTF therapy also involves the use of relatively highvoltages. For this reason, patients must be careful in performingeveryday activities having a risk of water exposure (e.g., showering,exercise (sweating), or even exposure to rain).

The use of electrodes in direct contact with the patient's skin presentsa risk of burning or heating of tissue adjacent to the electrodes.Because of this risk (and buildup of dirt, oils, etc.), the electrodesin TTF therapy systems typically require frequent replacement (e.g.,twice each week). Patients wearing TTF electrodes on the scalp reportedheadaches related to wearing the electrodes 24 hours a day.

TTF electrodes must also be placed by trained users (e.g., techniciansor physicians). Because the treatment is highly localized (i.e., betweenthe electrodes), precise location of the cancer/tumor must first beperformed, and the electrodes must be placed with a high degree ofaccuracy to create an electric field that passes through it. If theelectrodes are slightly off of optimal placement, the treatment mayresult in suboptimal results.

In addition, although the '289 patent discloses ambulatory embodiments(i.e., embodiments in which the patent can wear and use the system inperforming at least some ordinary non-stationary life activities such aswalking, driving, shopping, etc.), in practice the power requirements(e.g., high voltages) for generating appropriate electric fields (e.g.,at least 10 V/m) result in bulky and/or heavy electronics boxes thatmust be coupled to the electrodes and thus carried by the patient. Oneclinical study showed a relatively high rate of falls in patientscarrying these cumbersome TTF electronics boxes.

In view of these limitations to TTF systems, there is a need for safertherapies that may be applied for longer durations to destroy cancer orother rapidly-dividing cells. The many problems associated withelectrodes also raise a need for new therapies that avoid a risk of skinpain or the need for continuous contact with skin or other tissue.Because the efficacy of the system depends upon how long the electricfields can be applied to the rapidly-dividing cancer cells, less bulky,heavy, and cumbersome systems are needed to permit truly ambulatory,long duration treatments. Finally, there is a need for therapy systemsthat do not require trained patients or clinicians for setup.

SUMMARY

In one aspect, the present invention provides a method of treatingcancer cells in a target body area of a patient, comprising: providing amagnetic field therapy system comprising: an alternating polarity (AP)magnetic field generator; one or more AP electromagnetic coils coupledto the AP magnetic field generator, wherein the one or more APelectromagnetic coils are energized by an electrical signal from the APmagnetic field generator to generate an AP magnetic field having atleast a first frequency and a first field strength; and a controller tocontrol at least one of the first frequency and the first field strengthof the AP magnetic field generated by the one or more AP electromagneticcoils; coupling the one or more AP electromagnetic coils to the targetbody area; generating an AP magnetic field having a first frequency of0.1-500 kHz and a field strength of 0.2-5 mT using the one or more APelectromagnetic coils; applying the generated AP magnetic field to thetarget body area using the one or more AP electromagnetic coils, whereinthe AP magnetic field modifies the tumor microenvironment to achieve atleast one of: increasing the number of CD8+ lymphocytes in the TME;increasing the ratio of CD8+ to total lymphocytes in the TME; increasingthe number of CD4+ lymphocytes; increasing the ratio of CD4+ to totallymphocytes in the TME; increasing the number of tumor infiltratinglymphocytes (TILs) in the TME; increasing the number of antigenpresenting cells (APCs) in the TME; increasing the concentration oftumor-suppressive cytokines in the TME; decreasing the concentration oftumor-promoting cytokines in the TME; increasing the number of M1macrophages in the TME; decreasing the number of M2 macrophages in theTME; decreasing one of the number or concentration of myeloid-derivedsuppressor cells (MDSCs) in the TME; and increasing one of the number orconcentration of natural killer (NK) cells in the TME.

In another aspect, the present invention comprises a method of treatingcancer cells in a target body area of a patient, comprising: providing amagnetic field therapy system comprising: an alternating polarity (AP)magnetic field generator; one or more AP electromagnetic coils coupledto the AP magnetic field generator, wherein the one or more APelectromagnetic coils are energized by an electrical signal from the APmagnetic field generator to generate an AP magnetic field having atleast a first frequency and a first field strength; and a controller tocontrol at least one of the first frequency and the first field strengthof the AP magnetic field generated by the one or more AP electromagneticcoils; coupling the one or more AP electromagnetic coils to the targetbody area; generating an AP magnetic field having a first frequency of0.1-500 kHz and a field strength of 0.2-5 mT using the one or more APelectromagnetic coils; applying the generated AP magnetic field to thetarget body area using the one or more AP electromagnetic coils, whereinthe AP magnetic field modifies the tumor microenvironment to achieve atleast one of: modulating the blood vessels surrounding the cancer cells;modulating the presence of fibroblasts proximate to the cancer cells;modulating immune cell signaling molecules proximate to the cancercells; modulating the extracellular matrix surrounding the cancer cells;modulating resident host cells; modulating infiltrating host cells;modulating secreted factors proximate to the cancer cells; modulatingthe proteins surrounding the cancer cells; modulating the presence ofpericycles proximate to the cancer cells; and modulating the presence ofadipocytes proximate to the cancer cells.

In another aspect, the present invention provides a method of treatingcancer cells in a target body area of a patient, comprising: providingat least one electromagnetic coil; providing a controller coupled to theat least one electromagnetic coil; coupling the at least oneelectromagnetic coil to the target body area; applying to the targetbody area an alternating polarity (AP) magnetic field having a frequencyof 0.5-500 kHz and a field strength of 0.05-5 mT, wherein the APmagnetic field is generated by the at least one electromagnetic coilunder the control of the controller, and the AP magnetic fieldselectively affects the cancer cells to achieve at least one of damagingthe cancer cells, inhibiting the growth of the cancer cells, reducingtumor size, inhibiting angiogenesis, eliciting an immune response to thecancer cells, increasing tumor immunogenicity, decreasingimmunosuppressive activity of the cancer cells, recruiting one ofantigen-presenting cells and immune effector cells to the tumormicroenvironment, or preventing metastasis of the cancer cells, whileleaving non-cancer cells substantially unharmed.

In another aspect, the present invention provides a system for treatingcancer cells in a target body area of a patient comprising: at least oneelectromagnetic coil coupled to a target body area; and a controller forcontrolling the at least one electromagnetic coil to generate and applyto the target body area an AP magnetic field having a frequency of0.1-500 kHz and a field strength of 0.05-5 mT, wherein the AP magneticfield selectively affects the cancer cells to achieve at least one ofdamaging the cancer cells, inhibiting the growth of the cancer cells,reducing tumor size, inhibiting angiogenesis, eliciting an immuneresponse to the cancer cells, increasing tumor immunogenicity,decreasing immunosuppressive activity of the cancer cells, recruitingone of antigen-presenting cells and immune effector cells to the tumormicroenvironment (TME), or preventing metastasis of the cancer cells,while leaving non-cancer cells substantially unharmed.

In another aspect, the present invention provides a system for treatingcancer cells in a target body area of a patient comprising: at least oneelectromagnetic coil coupled to a target body area; a power supply forsupplying power to said electromagnetic coil; and a controller forcontrolling the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 0.1-500 kHz and a field strength of 0.1-5 mT, wherein theAP magnetic field modifies the tumor microenvironment (TME) by at leastone of: increasing the number of CD8+ lymphocytes in the TME; increasingthe ratio of CD8+ to total lymphocytes in the TME; increasing the numberof CD4+ lymphocytes; increasing the ratio of CD4+ to total lymphocytesin the TME; increasing the number of tumor infiltrating lymphocytes(TILs) in the TME; increasing the number of antigen presenting cells(APCs) in the TME; increasing the concentration of tumor-suppressivecytokines in the TME; decreasing the concentration of tumor-promotingcytokines in the TME; increasing the number of M1 macrophages in theTME; decreasing the number of M2 macrophages in the TME; decreasing oneof the number or concentration of myloid-derived suppressor cells(MDSCs) in the TME; and increasing one of the number or concentration ofnatural killer (NK) cells in the TME.

In another aspect, the present invention provides a system for treatingcancer cells in a target body area of a patient comprising: at least oneelectromagnetic coil coupled to a target body area; a power supply forsupplying power to said electromagnetic coil; and a controller forcontrolling the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 0.1-500 kHz and a field strength of 0.1-5 mT, wherein theAP magnetic field modifies the tumor microenvironment (TME) by at leastone of: modulating the blood vessels surrounding the cancer cells;modulating the presence of fibroblasts proximate to the cancer cells;modulating immune cell signaling molecules proximate to the cancercells; modulating the extracellular matrix surrounding the cancer cells;modulating resident host cells; modulating infiltrating host cells;modulating secreted factors proximate to the cancer cells; modulatingthe proteins surrounding the cancer cells; modulating the presence ofpericycles proximate to the cancer cells; and modulating the presence ofadipocytes proximate to the cancer cells.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic block diagram of a system for providing analternating polarity (AP) magnetic field to a target body area of apatient's body, according to one embodiment for selectively destroyingcancer cells.

FIG. 2 is a front view of a retaining element comprising a bra havingone or more AP electromagnetic coils for providing an AP magnetic fieldto breast tissue, according to one embodiment of the invention.

FIG. 3 is a front view of a retaining element comprising a hat includingone or more AP electromagnetic coils for providing an AP magnetic fieldto brain tissue, according to one embodiment of the invention.

FIG. 4 is a front view of a retaining element comprising a shirt havingone or more AP electromagnetic coils for providing an AP magnetic fieldto thoracic or abdominal tissue, according to one embodiment of theinvention.

FIG. 5 is a front view of a retaining element comprising a neck cuff orcollar having one or more AP electromagnetic coils for providing an APmagnetic field to a target area of a patient's body, according to oneembodiment of the invention.

FIG. 6 is a front view of a retaining element comprising a bandagehaving one or more AP electromagnetic coils for providing an AP magneticfield to a target area of a patient's body, according to one embodimentof the invention.

FIG. 7A is a photograph at 10× magnification of untreated B16F10 mousemelanoma cells incubated for 24 hours.

FIG. 7B is a photograph of B16F10 mouse melanoma cells exposed to an APmagnetic field for 24 hours according to one embodiment of theinvention.

FIG. 8 is a bar graph showing the reduction in cell counts of B16F10mouse melanoma cells treated with an AP magnetic field for 24 hourscompared to untreated controls.

FIG. 9 is a graph of tumor volume as a function of time from the startof a magnetic field tumor therapy in an experiment according to oneembodiment of the invention.

FIG. 10 is a schematic block diagram of one embodiment of a system forproviding an alternating polarity (AP) magnetic field to a target bodyarea of a patient's body for treating cancer cells.

FIG. 11 is a table summarizing the results of a number of experiments oncancer cells using alternating polarity (AP) magnetic field tumor (MFT)therapy.

FIG. 12 is a graph showing the increase in tumor volume over time forbreast cancer cells in an animal model experiment involving MFT therapy.

FIG. 13 is a graph showing the increase in tumor volume over time forcolon cancer cells in animals treated with an immunotherapy alone orcombined with MFT therapy.

FIG. 14 is a graph showing relative metastasis of breast cancer cells inanimals treated with MFT therapy, an immunotherapy, or combined MFTtherapy and immunotherapy.

FIG. 15 is a graph showing relative changes of CD8+ T cells in the tumormicroenvironment of breast cancer cells in animals treated with MFTtherapy, an immunotherapy, or combined MFT therapy and immunotherapy.

FIG. 16 is a graph showing relative changes of myeloid-derivedsuppressor cells (MDSCs) in the tumor microenvironment of breast cancercells in animals treated with MFT therapy, an immunotherapy, or combinedMFT therapy and immunotherapy.

FIG. 17 is a graph showing relative changes of dendritic cells (DCs) inthe tumor microenvironment of breast cancer cells in animals treatedwith MFT therapy, an immunotherapy, or combined MFT therapy andimmunotherapy.

DESCRIPTION

Exemplary embodiments of the present disclosure are illustrated in thedrawings, which are illustrative rather than restrictive. No limitationon the scope of the technology or on the claims that follow is to beimplied or inferred from the examples shown in the drawings anddiscussed here.

In some embodiments, the invention provides apparatus and methods fortreating a patient having cancer or other rapidly dividing cells (e.g.,bacterial infection) in a target body area using alternating polarity(AP) magnetic fields at specified frequencies to destroy or inhibit theproliferation of the rapidly dividing cells. The use of electric fields,including without limitation TTF systems, to treat patients havingcancer or other diseases characterized by rapidly-dividing cells has anumber of limitations that make treatment for some patients difficult,ineffective, painful, or unsafe. Embodiments of the present inventionovercome one or more of these limitations by using AP magnetic fields totreat rapidly-dividing or hyperproliferating cells.

As used herein, the terms “magnetic field tumor (MFT) therapy” and“MFTT” refer to systems and methods for treating cancer or otherrapidly-dividing cells with AP magnetic fields at specified frequenciesand magnetic field strengths to destroy or inhibit the proliferation ofsuch cells. In various embodiments, the present invention may be used totreat one or more cancers such as throat cancer, thyroid cancer, mouthcancer, nose cancer, salivary gland cancer, lung cancer, lung carcinoidtumors, thymic malignancies, tracheal tumors, pancreatic cancer, livercancer, stomach cancer, kidney cancer, ovarian cancer, prostate cancer,colon cancer and rectal cancer.

As used herein with respect to one kind of MFT therapy, the term “dutycycle” refers to the fraction of a time period in which an alternatingpolarity magnetic field is applied to the target body area. The dutycycle may be calculated by the formula

$ {{{duty}{cycle}} = \frac{{on}{time}}{( {{{on}{time}} + {{off}{time}}} }} )$

where on time is the period for which the magnetic field is applied tothe target body area, and off time is the time following the on timethat no magnetic field is applied to the target body area. In oneembodiment, the MFT therapy is applied in repeating cycles of on timefollowed by off time. In a particular example, an 80% duty cycle mayinvolve 8 hrs in which an alternating polarity magnetic field is appliedto the target body area, followed by 2 hrs in which no magnetic field isapplied. It will be appreciated that the same duty cycle can be achievedover different time frames, for example 8 minutes on time followed by 2minutes off time, or 8 days on time followed by 2 days off time.

FIG. 1 is a simplified schematic block diagram illustrating certaincomponents of an MFT therapy system 100 according to an embodiment ofthe invention. The MFT therapy system 100 includes an alternatingpolarity magnetic field generator (APMFG) 110 to generate an electricalsignal to energize one or more alternating polarity (AP) electromagneticcoils 120 to produce an AP magnetic field having specified frequency andfield strength characteristics. In one embodiment, the APelectromagnetic coils 120 may have sizes and shapes adapted to engageone or more target body areas of a patient (e.g., torso, breast, head,neck, throat) for treatment of cancer or hyperproliferating cells in thetarget body area. The electrical signals generated by APMFG 110 andapplied to AP electromagnetic coils 120 is controlled by a controller130, which specifies the parameters of the magnetic fields to begenerated by APMFG 110 and AP electromagnetic coils 120, and controlsthe function and operation of the system 100. An interface 140 isprovided to allow a user to specify treatment parameters to beprogrammed or communicated to the controller 130, and to receiveinformation from the controller relating to the operation and status ofthe MFT therapy system 100. A power supply 150 provides power to MFTtherapy system 100. Power supply 150 may be selected from a variety ofknown power supplies, and may comprise, in various embodiments, abattery such as a disposable or rechargeable battery, or a power sourcesuch as a standard 120V, 60 Hz electrical power outlet in the US,together with circuitry for regulating the power at appropriate currentsand voltages for each of the APMFG 110, AP electromagnetic coils 120,controller 130, and interface 140.

Controller 130 may include circuitry and other components (e.g.,microcontrollers, resistors, registers, memory, firmware, software,etc.) to direct and control the operations of the APMFG 110, APelectromagnetic coils 120, and interface 140. FIG. 1 illustrates anembodiment in which the AP electromagnetic coils 120 are energizeddirectly from the magnetic field generator. In an alternative embodiment(not shown), controller 130 may communicate directly with each of theone or more AP electromagnetic coils 120 to control their operation inwhole or in part (e.g., by switches that enable or disable each APelectromagnetic coil 120).

Controller 130 includes a timing control module 112 for controlling thetiming of the MFT therapy delivered by AP electromagnetic coil(s) 120 toone or more target body areas or tissues. In various embodiments, timingcontrol module 112 may cause the AP magnetic field generator 110 and APelectromagnetic coils 120 to provide MFT therapy for a programmedduration such as 1-100 hours or other treatment period, or the timing ofand between a plurality of therapy treatment periods. For example, thetiming control module 112 may implement a first therapy for a first timeperiod (e.g., during waking hours of the patient) at a first frequencyand field strength, followed by a second time period in which no therapyis applied, followed by a third time period in which a second therapy isimplemented at a second frequency and second field strength. Timingcontrol module 112 may also control the timing of changes in othertreatment parameters, such as changes in the frequency or field strengthof the MFT therapy applied to the patient.

A frequency control module 114 controls the frequency of the AP magneticfields delivered by AP electromagnetic coil(s) 120 to the one or moretarget body areas or tissues. Frequency control module 114 may controlthe frequency of the AP magnetic field at a programmed frequency of0.5-500 kHz. In some embodiments, the frequency control module 114 maycontrol frequency changes to the AP magnetic fields generated by theAPMFG 110 and the AP electromagnetic coils 120 at a programmed rate ofchange or according to specific frequency step changes.

A magnetic field strength control module 116 controls the field strengthof the AP magnetic fields applied to the one or more target body areas.Magnetic field strength control module 116 may control the fieldstrength at a programmed magnetic field strength of 0.05-5 mT, and maycontrol changes in the field strength according to a programmed rate ofchange or programmed step changes in field strength.

Controller 130 may include programming logic, timers, and othercircuitry to accomplish the functions of the timing control module 112,frequency control module 114, and magnetic field strength control module116. It will be appreciated in alternative embodiments, the functions ofall or portions of timing control module 112, frequency control module114, and magnetic field strength control module 116 may be combined intoone or more submodules, or implemented by controller 130 as a whole.

In one embodiment, interface 140 may include a user input, such as akeyboard or buttons, to allow a user to input or receive data fromcontroller 130. In a further embodiment (not shown) interface 140 may belocated within controller 130 and may comprise a transceiver tocommunicate with a separate user device (not shown) such as a cellphone, tablet, or other computing device to program the MFT therapysystem 100 and receive data therefrom (e.g., operating and alarm statusflags, programmed parameters, treatment time, etc.). In otheralternative embodiments (not shown), interface 140 may be omitted, ormay be incorporated as part of a single unit having some or all of thefunctions of AP magnetic field generator 110, controller 130, andinterface 140.

Referring again to FIG. 1, in various embodiments the APMFG 110 mayprovide an electrical signal to cause each of the one or more APelectromagnetic coils 120 to generate magnetic fields having one or morefixed or variable AP frequencies. Although shown in the simplifiedschematic diagram of FIG. 1 as coupled to APMFG 110 by a single wire, itwill be understood that each of AP electromagnetic coils 120 willgenerally be coupled to APMFG 110 by a pair of wires (not shown) toprovide a complete circuit. In fixed-frequency embodiments, APMFG 110may cause each of the one or more AP electromagnetic coils 120 togenerate a magnetic field having a single frequency or a plurality offrequencies either continuously or intermittently according to a definedduty cycle (e.g., having a programmable on-time during which themagnetic field is emitted from AP electromagnetic coils 120, followed byan off-time during which no field is emitted). The APMFG 110 may alsocause the one or more AP electromagnetic coils 120 to generate APmagnetic fields having a variety of waveforms, e.g., sinusoidal,triangular, trapezoidal etc. In some embodiments the APMFG 110 may causethe one or more AP electromagnetic coils 120 to generate AP magneticfields having a pre-defined number of waveforms of a specified firstfrequency, and repeat this pattern at a second specified frequency(burst mode). In other embodiments, the APMFG 100 may cause the one ormore AP electromagnetic coils 120 to generate a magnetic field having awaveform which uses a fixed frequency or a combination of frequenciescoupled with amplitude modulation.

Whether fixed or variable, the frequency (or frequencies) of the APmagnetic fields generated by each AP electromagnetic coil 120 arepreferably frequencies below about 1 MHz, and more preferably arefrequencies within a range selected from 0.1-500 kHz, 0.2-400 kHz,0.5-300 kHz, 1-200 kHz, 5-150 kHz, 10-100 kHz, or 25-100 kHz. In oneembodiment, the MFT therapy system 100 may comprise at least two APelectromagnetic coils 120, each having a fixed or variable frequencywithin a different frequency range to provide magnetic fields atmultiple frequencies to a target body area or tissue. For example, APMFT110 may generate a first electrical signal to cause a first APelectromagnetic coil 120 to generate an AP magnetic field with a firstfixed frequency or a variable first frequency within a first frequencyrange, and a second electrical signal to cause a second APelectromagnetic coil 120 to generate an AP magnetic field with a secondfixed frequency or a variable second frequency within a second frequencyrange, where both the first frequency range and the second frequencyrange are ranges within the range of 0.1-500 kHz, 0.2-400 kHz, 0.5-300kHz, 1-200 kHz, 5-150 kHz, 10-100 kHz, or 25-100 kHz. As a nonlimitingexample, the first frequency range may be a low-frequency range (e.g.,1-5 kHz) and the second frequency range may be a higher-frequency range(e.g., 50 kHz-300 kHz).

Without being bound by theory, it is believed that AP magnetic fieldswithin a plurality of frequency sub-ranges within the range of 0.5-500kHz may affect different aspects of the reproduction cycle ofrapidly-dividing cells, and that each such aspect may be more stronglyaffected by AP magnetic fields within a particular frequency sub-rangewithin the broader range of 0.5-500 kHz. For example, the interruptionof angiogenesis by extremely low frequency AP magnetic fields has beenreported for AP magnetic fields having a frequency of 50 Hz (Monache etal., “Inhibition of Angiogenesis Mediate by Extremely Low-FrequencyMagnetic Fields (ELF-MFs),” PLOS One, 8:11 (November 2013). Differenttypes of cells, including without limitation different types of cancercells, may require different frequencies for interruption ofangiogenesis.

Accordingly, in one embodiment an MFT therapy having a bimodal magneticfield frequency distribution may be applied to the target body area. Inone exemplary embodiment, the APMFT 110 may generate a first electricalsignal to cause a first AP electromagnetic coil 120 to generate a firstvariable AP magnetic field distribution that varies the magnetic fieldfrequency over a first time period (e.g., 1 second, 1 minute, 10minutes, 1 hr) between a first lower limit (e.g., 0.5 kHz) and a firstupper limit (e.g., 5 kHz) to broadly interrupt a first metabolic process(e.g., angiogenesis) in a target cell population, as defined byfrequency control module 114. The APMFT 110 may also generate a secondelectrical signal to cause the same or a second AP electromagnetic coil120 to generate a second variable AP magnetic field distribution thatvaries the magnetic field frequency over a second time period (e.g., 1second, 1 minute, 10 minutes, 1 hr) between a second lower limit (e.g.,50 kHz) and a second upper limit (e.g., 400 kHz) to broadly interrupt asecond metabolic process (e.g., the mitosis cycle) of rapidly-dividingcells. Additional coils may produce different fixed orvariable-frequency AP magnetic fields having different frequencies orfrequency ranges to interrupt still other aspects of the reproductioncycle of rapidly-dividing cells. In an alternative example, a single APelectromagnetic coil 120 may be used to sequentially deliver AP magneticfields within two different AP frequency ranges (e.g., 1-5 kHz for afirst treatment period, followed by 50-400 kHz for a second treatmentperiod).

In variable-frequency embodiments, many different ways of implementing achanging frequency are possible, and enumeration herein of specificembodiments of varying frequencies is illustrative and is not intendedto be limiting. It will be appreciated that additionalvariable-frequency embodiments may be implemented in view of the presentdisclosure. In one embodiment, a magnetic field may be generated havinga single frequency that varies from a lower frequency (e.g., 25 kHz) toan upper frequency (e.g., 150 kHz) in a uniform manner (i.e.,non-varying rate of frequency change) within a defined frequency rangetime period or at a desired (e.g., programmed) frequency change rate. Inanother embodiment, the frequency may vary in a non-uniform manner suchas stepwise changes in frequency or different rates of change (e.g.,rates of change of frequency are highest near the mid-point between theupper and lower frequency limits). In a still further embodiment, thefrequency may vary continuously or intermittently, withvariable-frequency periods alternating with non-variable frequencyperiods. In additional embodiments, a field having two differentfrequencies may simultaneously be applied to the target body area(emitted, e.g., by a single coil or by two different coils). Byproviding multiple (e.g., 2 or more) coils, MFT therapies having adesired frequency distribution (e.g., random, Gaussian, or non-Gaussian)either sequentially or simultaneously may be applied to one or moretarget areas.

The electrical signal from APMFG 110 to AP electromagnetic coils 120also defines the field strength of the AP magnetic fields produced bythe coils, as defined by magnetic field strength control module 116. MFTtherapy systems 100 of the present invention may use relatively lowmagnetic field strengths to destroy or impair rapidly-proliferatingcells. Preferably, MFT therapy fields in systems 100 of the presentinvention have field strengths of less than 5 milliTesla (i.e., 5,000μT), such as field strengths within a range selected from 0.1-5 mT,0.2-4 mT, 0.4-3 mT, 0.5-2 mT, or 0.8-1.6 mT. In a preferred embodiment,the field strengths are within the range of 0.2-4 mT, and morepreferably within the range of 0.5-2 mT. Table 1 summarizes frequencyand field strength ranges according to various embodiments of theinvention. In various embodiments, additional frequency ranges can beprovided using upper or lower boundaries from different ranges providedin the table.

TABLE 1 Frequency range (kHz) Field strength range (mT) 0.1-500  0.1-50.2-400 0.2-4 0.5-300 0.4-3  1-200 0.5-2  5-150  0.1-1.6  10-100  25-100

In one embodiment, the magnetic field may have a single, non-varyingfield strength. Without being bound by theory, it is believed thatdifferent cell sizes (e.g., different types of cancers) may requiredifferent field strengths for maximum efficacy in destroying orinhibiting cell division. Within such embodiments, however, the APmagnetic fields may have a single, non-varying field strength eithercontinuously or intermittently according to a defined duty cycle asdefined by, e.g., timing control module 112 and magnetic field strengthcontrol module 116.

In variable-field-strength embodiments, many different ways of varyingthe field strength can be envisioned, similar to the variationsdescribed above respecting frequency changes. As with frequency,enumeration herein of specific embodiments of varying field strength isillustrative, not limiting. Additional variable-field-strengthembodiments may be implemented (e.g., by magnetic field strength controlmodule 116) in view of this disclosure. In one embodiment, a magneticfield may have a field strength that varies from a lower limit (e.g.,0.05 mT) to an upper limit (e.g., 1 mT) in a uniform manner (i.e., witha non-varying rate of change) within a defined field strength range timeperiod. In another embodiment, the field strength may vary in anon-uniform manner such as stepwise changes in field strength or with aswept field strength variation with accelerating or decelerating fieldstrength variation (e.g., rates of change of field strength are highestnear the upper and lower limits of the field strength range). In a stillfurther embodiment, magnetic field strength may vary continuously orintermittently, with variable-field-strength periods alternating withnon-variable-field-strength periods. In some embodiments, AP magneticfields at two different frequencies, each having a different fieldstrength, may simultaneously be applied to the target body area(emitted, e.g., by two different AP electromagnetic coils 120). Byproviding multiple AP electromagnetic coils 120, MFT therapies having adesired frequency and magnetic field strength distribution (e.g.,random, Gaussian, or non-Gaussian), either sequentially orsimultaneously may be applied to the target body area.

To optimize therapeutic efficacy and patient tolerance, in someembodiments the therapy is suspended for certain periods. This mayinvolve, for example, providing MFT therapy continuously with definedalternating on-time (e.g., a time period within a range of 1 sec-24 hr)and off-time (e.g., 1 sec-24 hr) periods according to a definedtreatment duty cycle as defined by timing control module 112. In oneembodiment, the on-time and off-time periods may be a time period withina range of 1 second-1 week, 1 sec-24 hr, 1 minute-12 hr, etc.). In onesuch exemplary embodiment, the MFT therapy is provided continuously at a10:1 duty cycle by generating and applying the MFT therapy fields forten (10) minutes, followed by 1 minute in which no therapy is applied,with the process repeated until a predefined total treatment duration(e.g., 2 weeks) is complete. In another embodiment, the same 10:1 dutycycle may be administered by applying the MFT therapy fields for tenhours, followed by a one-hour suspension of therapy, and repeating theprocess until the total treatment period is complete.

In another embodiment, MFT therapy according to a defined treatment dutycycle comprising on-time and off-time periods may be administered for adefined treatment duration (e.g., 1 minute, 1 hr, 6 hr, 8 hr, 24 hr)after which no further treatment is applied. In a still furtherembodiment, the MFT therapy may be administered according to thepatient's circadian rhythms (e.g., continuously at night or when thepatient is sleeping, and according to a defined duty cycle for definedperiods during the day such as morning hours, afternoon hours, orevening hours). It will be appreciated that other duty cycles andtreatment durations may be used, and that the therapy may involve, aspreviously discussed, constant or variable magnetic field frequenciesand field strengths.

In another embodiment, MFT therapy may be applied according to a definedtreatment duty cycle of on-time and off-time periods, with the magneticfield strength varying according to a defined field strength duty cycle.This may involve, for example, a 10:1 treatment duty cycle combined witha 4:1 field strength duty cycle. As a specific example, the MFT therapymay be provided for a 24 hr treatment duration, at a 10:1 treatment dutycycle with AP magnetic fields applied to a target body area for 10minutes, followed by 1 minute in which no AP magnetic fields areapplied. Within the 10-minute treatment periods, 8 minutes may involvevariable frequency treatment within a first field strength range of3.0-4.0 mT, followed by 2 minutes of treatment within a second fieldstrength range of 0.5-1.5 mT, providing a 4:1 field strength duty cycle.

In a further embodiment, the AP magnetic fields in a mode known as“pulse mode” or “burst mode” in which pulses at a defined low frequency(the “pulse frequency”) and pulse duration are applied to a target bodyarea, but each pulse comprises a higher frequency magnetic field signalat a frequency within a frequency range and field strength rangepreviously described. In one nonlimiting example, AP magnetic fieldpulses at a pulse frequency of 50 Hz, with each pulse having a pulseduration of 10 msec, are applied in which each 10 msec pulse comprisespulses having a higher frequency of 100 kHz. Table 2 summarizes theexemplary pulse frequency and pulse durations for burst mode operation.Frequencies and field strengths within each pulse of Table 2 would be asshown in Table 1.

TABLE 2 Pulse frequency (Hz) Pulse duration (msec) 0.01-1000  0.1-50000.1-500  1-1000  1-200 10-800  2-100 50-500  5-50 60-300 100-500 200-1000 500-2000    1-10,000  100-2,000 1,000-2,000 

In alternative embodiments, MFT therapy fields may be applied accordingto the patient's circadian rhythms, or according to specific times ofday. For example, the MFT therapy fields may be applied to the targetbody area only during daytime hours; only during nighttime hours; duringall daytime hours except during mealtime hours; during all daytime hoursexcept when the patient is exercising (as detected by, e.g., an activitymonitor); during specific hours of the day (e.g., 9:00 AM-noon and 6:00PM-5:00 AM). These examples are intended to be exemplary only, and itwill readily be appreciated that delivery of MFT therapy fields can betailored to suspend therapy during certain hours that would be mostconvenient to the patient, while also minimizing damage to normal (i.e.,non-rapidly-dividing) cells.

Most magnetic field-generating coils are constructed so as to generate amagnetic field having an axis along which the magnetic field lines aredirected. In some embodiments, multiple AP magnetic coils 120 can bespatially aligned in such a manner that a desired magnetic fielddistribution is generated in area of interest, such as the entirety or aportion of the target body area.

In some embodiments, one or more parameters defining the MFT therapy(e.g., frequency, field strength, selection of specific coils among aplurality of available coils) may be determined based on the results ofcertain tests. For example, an imaging procedure may be performed toidentify the type and location of the target rapidly-dividing cells(e.g., cancer or tumor cells). In various embodiments, the imagingprocedure may be an imaging procedure using one or more of an MRIsystem, a CT scan system, a PET scan system, and an X-ray system.

Based on the results of the imaging (e.g., cell size(s), type of cells,location of cells, etc.) a healthcare provider such as a physician mayselect one or more parameters of the MFT therapy, including withoutlimitation, the frequency/frequencies of the magnetic field(s), thefield strength(s), the positioning of one or more coils, a coil size, atype of retaining element (e.g., a garment type) to maintain the coilsin position relative to the target body area, a duty cycle or schedulefor applying therapy, etc. It will be appreciated that the foregoing andother parameters may also be selected based on other tests, e.g., apathological analysis of the cancer cells such as a microscopic analysisof a biopsy, a chemical test, a genetic test, etc.

In some instances, the results of an imaging procedure prior to the MFTtherapy may identify a target body area to which MFTT is to be directed.Based on the location of the target body area, in some embodiments aretaining element may be necessary to retain the magnetic coils in adesired position relative to the target treatment area or tissue.Various retaining elements may be used to unobtrusively and securelymaintain the magnetic coils in a desired position relative to a desiredtarget area of the patient's body. For example, a bra may be used tohouse the magnetic coils for treatment of breast cancer cells. Inanother example, a hat may be used to retain magnetic coils in positionto treat brain cancer. In still another example, a neck cuff, collar, orscarf may retain one or more magnetic coils for treatment of esophagealcancer, and a shirt may be used to retain one or more magnetic coils totreat lung cancer. In another embodiment, the retaining element may be abandage such as an adhesive bandage capable of adhering to the targetbody area or to skin adjacent thereto. These examples are exemplary andnot limiting, and it will be appreciated that a variety of other oradditional retaining elements may be used depending upon the targettissue location. Because the magnetic coils do not need to be in directcontact with the skin of the patent, the retaining elements may includepouches or pockets for securely retaining the coils in position with acomfortable and biocompatible lining placed between the coil and theskin or target treatment area. In some embodiments, the APelectromagnetic coils 120 are completely integrated within the retainingelement during manufacturing (e.g., the coils are completely integratedinside a garment such as a bra, hat, shirt, bandage, etc.) In variousembodiments, the retaining element may include a lead wire for couplingeach of the one or more coils 120 to the AP magnetic field generator 110and/or controller 130. In alternative embodiments, a direct electricalcoupling (e.g., a snap fit) may be used between an electronics packageand the AP electromagnetic coil(s) 120. The electronics package mayinclude one or more of the power supply 150, controller 130, APMFG 110,and interface 140.

FIG. 2 illustrates a bra 200 that acts as a retaining element for one ormore magnetic coils 220 for applying one or more magnetic fields to atarget body area to treat cancer cells or other rapidly-dividing cellsin breast tissue. Magnetic coils 220 may be the same as coils 120described in FIG. 1, but may be adapted for placement in bra 200 (e.g.,with a size, geometry, etc., for treatment of breast tissue). Bra 200may in many aspects be constructed similarly to existing bras availableat retail clothing outlets, and may include cups 210 for holding breasttissue and retaining coils 220 in position relative to a target bodyarea comprising breast tissue. Straps 230 may be provided to secure thebra 200 to the shoulders of the patient, and side straps or bands 240for securing the bra to the patient's torso. AP electromagnetic coils220 may be integrated into bra 200, or may be removably coupled thereto.

One or more cables or wires 250 may be provided to couple each of thecoils 220 to an electronics box 260, which may house the remainingcomponents of the MFT therapy system 100 of FIG. 1 such as APMFG 110,controller 130, power supply 150, and in some embodiments interface 140.In alternative embodiments, one or more of the APMFG 110, controller130, power supply 150, or interface 140 may be provided separately fromthe electronics box 260. For example, interface 140 may comprise amobile phone app that communicates directly with one or more of APMFG110, controller 130, power supply 150, etc., as well as receiving anddisplaying information from one or more of the foregoing systemcomponents. The mobile phone app interface may allow the patient or ahealthcare provider to program one or more treatment parameters for theMFT therapy system 100, and may display information relating to the MFTtherapy or system 100 status (e.g., displaying how long the MFT therapyhas been applied, whether a magnetic field is currently being applied tothe target tissue from each of the coils 220, the frequency and/or fieldstrength of the currently-provided magnetic fields, remaining batterylife, etc.).

FIG. 3 illustrates a hat 300 that acts as a retaining element for one ormore AP electromagnetic coils 320 for applying one or more magneticfields to the treatment of cancer or other rapidly-dividing cells in atarget body area comprising brain tissue. Magnetic coils 320 are, in oneembodiment, similar to AP electromagnetic coils 120 described in FIG. 1,but may be adapted for placement in hat 300. This may include changes inthe size, geometry, or other characteristics to enable effectiveplacement in hat 300 for treatment of brain tissue. In variousembodiments, methods and systems of the present invention may be used totreat a variety of brain cancers, including without limitationastrocytomas, glioblastoma multiforme, meningioma, and pituitary tumors.Although depicted as a baseball cap, it will be apparent that many otherhead coverings, hat types and styles may be used for hat 300 (e.g.,skullcap, beret, fedora, etc.). In one embodiment, hat 300 may be askullcap of an appropriate size to fit closely on the head of thepatient, and the magnetic coils 320 may have a concave shape adapted forlocation or placement in the cap, e.g., inside the hat or in a pocketbetween an inner and outer layer thereof. AP electromagnetic coils 320may be integrated into hat 300, or may be removably coupled thereto.

One or more cables or wires 350 may be provided to couple each of the APcoils 320 to an electronics box 360, which may house the remainingcomponents of the MFT therapy system 100 of FIG. 1 such as APMFG 110,controller 130, power supply 150, and in some embodiments interface 140.In alternative embodiments, one or more of the APMFG 110, controller130, power supply 150, or interface 140 may be provided separately fromthe electronics box 360. For example, as described in connection withFIG. 2, a separate interface 140 may be provided as a mobile phone appthat communicates directly with one or more of APMFG 110, controller130, power supply 150, etc. Such an app-based interface may also provideinformation on the MFT therapy to the patient or a healthcare provider(e.g., displaying how long the MFT therapy has been applied, whether amagnetic field is currently being applied to the target tissue from eachof the coils 320, the frequency and/or field strength of thecurrently-provided magnetic fields, remaining battery life, etc.).

FIG. 4 illustrates a shirt 400 that acts as a retaining element for oneor more AP electromagnetic coils 420 for applying one or more magneticfields to the treatment of cancer or other rapidly-dividing cells in atarget tissue in a patient's thoracic or abdominal region. This mayinclude, without limitation and depending on the placement of the one ormore AP electromagnetic coils 420, treatment of lung cancer, livercancer, pancreatic cancer, or cancers or tumors in other thoracic orabdominal organs or structures. AP electromagnetic coils 420 are, in oneembodiment, similar to coils 120 described in FIG. 1, but may be adaptedfor placement in shirt 400 based on the target tissue. This may includechanges in the coil size, geometry, or other characteristics to enableeffective placement in shirt 400 and for treatment of the particulartarget tissue. Although depicted as a T-shirt, that many other types andstyles of shirt may be used as shirt 400, including long-sleeve or shortsleeve shirts; button, zip, or pullover shirts. In addition, it will beunderstood that shirt 400 may comprise other garments that may cover thethoracic or abdominal region of a patient, including sweaters, jackets,coats, etc., although in preferred embodiments a shirt that fits tightlyto the patient's body is used to better retain the AP electromagneticcoils 420 in a more precise or controlled placement relative to thetarget tissue. AP electromagnetic coils 420 may be adapted for locationor placement on the inside, outside or in a pocket of shirt 400, and maybe integrated into or removably coupled thereto.

One or more cables or wires 450 may be provided to couple each of thecoils 420 to an electronics box 460, which may house the remainingcomponents of the MFT therapy system 100 of FIG. 1 such as APMFG 110,controller 130, power supply 150, and in some embodiments interface 140.In alternative embodiments, one or more of the APMFG 110, controller130, power supply 150, or interface 140 may be provided separately fromthe electronics box 460. For example, a separate interface 140 may beprovided as a mobile phone app that communicates with one or more ofAPMFG 110, controller 130, power supply 150, etc. Such an app-basedinterface may also provide information on the treatment therapy to thepatient or a healthcare provider (e.g., displaying how long the therapyhas been applied, whether a magnetic field is currently being applied tothe target tissue from each of the coils 420, the frequency and/or fieldstrength of the currently-provided magnetic fields, remaining batterylife, etc.).

FIG. 5 illustrates a neck cuff or collar 500 that acts as a retainingelement for one or more AP electromagnetic coils 520 for applying one ormore magnetic fields to the treatment of cancer or otherrapidly-dividing cells in a target tissue in a patient's neck area,including without limitation esophageal cancer, laryngeal cancer, etc.AP electromagnetic coils 520 may be similar to coils 120 described inFIG. 1, but may be adapted for placement in neck cuff or collar 500based on the target treatment area or tissue. This may include changesin the size, geometry, or other characteristics to enable effectiveplacement in neck cuff 500 and for treatment of the particular targettissue. Neck cuff or collar 500 preferably includes a securing and/oradjustment tab 530 (e.g., Velcro) to adjust the cuff or collar to thepatient's size and to secure it in a fixed position relative to thepatient's neck. In one alternative embodiment, a neck scarf may be usedas a retaining element. AP electromagnetic coils 520 may be adapted forlocation or placement on the inside, outside or in a pocket of neck cuffor collar 500, and may be integrated into or removably coupled thereto.

One or more cables or wires 550 may be provided to couple each of thecoils 520 to an electronics box 560, which may house the remainingcomponents of the MFT therapy system 100 of FIG. 1 such as APMFG 110,controller 130, power supply 150, and in some embodiments interface 140.In alternative embodiments, one or more of the APMFG 110, controller130, power supply 150, or interface 140 may be provided separately fromthe electronics box 560. For example, a separate interface may beprovided as a mobile phone app that communicates with one or more ofAPMFG 110, controller 130, power supply 150, etc. Such an app-basedinterface may also provide information on the treatment therapy to thepatient or a healthcare provider (e.g., displaying how long the therapyhas been applied, whether a magnetic field is currently being applied tothe target tissue from each of the coils 520, the frequency and/or fieldstrength of the currently-provided magnetic fields, remaining batterylife, etc.).

FIG. 6 illustrates a bandage 600 that acts as a retaining element forone or more magnetic coils 620 for applying one or more magnetic fieldsto the treatment of cancer or other rapidly-dividing cells in a targettissue anywhere on the body. Magnetic coils 620 may be similar to thosedescribed in FIG. 1, but may be adapted for placement in bandage 600based on the target tissue. This may include changes in the size,geometry, or other characteristics to enable effective placement inbandage 600 and for treatment of any of a variety of different targettissues. Magnetic coils 620 may be adapted for location or placement onthe inside, outside or in a pocket of bandage 600, and may be integratedinto or removably coupled thereto.

One or more cables or wires 650 may be provided to couple each of thecoils 620 to an electronics box 660, which may house the remainingcomponents of the MFT therapy system 100 of FIG. 1 such as APMFG 110,controller 130, power supply 150, and in some embodiments interface 140.In alternative embodiments, one or more of the APMFG 110, controller130, power supply 150, or interface 140 may be provided separately fromthe electronics box 560. For example, a separate interface may beprovided as a mobile phone app that communicates with one or more ofAPMFG 110, controller 130, power supply 150, etc. Such an app-basedinterface may also provide information on the treatment therapy to thepatient or a healthcare provider (e.g., displaying how long the therapyhas been applied, whether a magnetic field is currently being applied tothe target tissue from each of the coils 620, the frequency and/or fieldstrength of the currently-provided magnetic fields, remaining batterylife, etc.).

Certain embodiments of the retaining element may also provide additionalfeatures to enable the MFT therapy to be conveniently delivered to thetarget body area or tissue. In one embodiment, the retaining element mayhave integrated magnetic coils 120, APMFG 110, and controller 130,either as separate items in the retaining element or as a single unit. Awire (not shown) may be provided to couple the power supply to one ormore of the APMFG 110, coils 120, controller 130, and interface 140. Inone embodiment, the power supply 150 provides power to the controller,which includes circuitry (e.g., rectifiers, converters, transformers,etc.) to modify the electrical power received from the power supply toprovide electrical power to controller 130, which in turn distributespower to the APMFG 110, AP electromagnetic coils 120, and interface 140.In this embodiment, a power supply (e.g., a battery) may be locatedelsewhere in close proximity to the patient (e.g., in a pocket in thepatient's trousers or a jacket).

In some embodiments, the MFT therapy may be provided to a patient incombination with one or more other therapies such as an anti-cancerdrug, radiation therapy, or TTF therapy (e.g., therapy as described inU.S. Pat. No. 6,868,289 or 8,019,414). The MFT therapy system 100preferably permits the other (i.e., non-MFT) therapy to be provided at alower dosage than would be administered in the absence of the MFTtherapy to the target body area or tissue, or at a reduced frequencythan would be administered in the absence of the MFT therapy, or both.In various embodiments, the co-therapy applied with the MFT therapy maybe a drug selected from a chemotherapy drug, a hormone receptor drug,targeted therapy drugs, immunotherapy, angiogenesis inhibitor drugs, acheckpoint inhibitor drug, and a HER2 receptor drug. In otherembodiments the co-therapy may be a radiation therapy selected from aninternal radiation therapy and an external beam radiation therapy. Instill other embodiments, the co-therapy applied with the MFT therapy maybe a TTF therapy involving the application of electrical fields to thetarget tissue. Without being bound by theory, it is anticipated that oneor more co-therapies (or adjuvant therapies), when combined with MFTtherapy, may achieve superior results than either therapy whenadministered alone. In various embodiments, the combination therapy maycomprise administering MFT therapy with an anti-cancer drug, radiation,or TTF therapy either simultaneously or sequentially.

It may be desirable in some instances to shield non-target body areasfrom the MFT therapy fields. In such instances an optional magneticfield shield (not shown) may be provided to shield the non-target areasfrom the effects of the magnetic fields. In some embodiments, highlylocalized shields may be provided to shield specific structures withinthe target body area of the patient, such as specific blood vessels ororgan structures that are adjacent to the target rapidly-dividing cells.

It is known that electric fields induce magnetic fields and vice versa.However, without being bound by theory, the present invention involvingMFT therapy appears to provide a therapy having a different mode ofaction than prior art TTF and/or drug therapies. In particular, TTFtherapies use capacitive electrodes to induce primarily electric fieldsat relatively high electric field strengths. According to reportedliterature (e.g., Kirson et al., Cancer Research 2004) TTF therapiesbegin to inhibit tumor cell growth at a field strength of about 100 V/mat frequencies of 50-250 kHz. In one recent experiment (see Experiment 1below), MFT therapies showed surprising results with a similarinhibition of tumor cell growth as reported for TTF therapies but at afraction (e.g., less than 3%) of typical TTF therapy electric fieldstrengths. In addition, the experimental results discussed hereinaftersuggest that efficacious frequencies for TTF and MFT therapies aredifferent as well.

Experiment 1

Mouse melanoma cells (B16F10 cell line, obtained from the University ofCalifornia-Berkeley) were incubated in Dulbecco's Modified Eagle Medium(DMEM) in 36 middle wells (5.0 mm diameter) of a 96 well plate for 24hours at 37° C. The cells in each of the 36 treatment wells were thenexposed for 24 hours to an alternating magnetic field at a frequency of150 kHz and a magnetic field strength of approximately 0.8 mT using aHelmholtz coil, maintained at a temperature of 37° C. Control wells werenot exposed to the alternating magnetic field and were incubated at 37°C. for the same time period. After 24 hours, the alternating magneticfield was discontinued and histology was performed for cells in eachwell (both treatment and control). FIGS. 7A and 7B are illustrative ofthe differences between typical control and treatment wells. Controlsexhibited a significantly higher cell count per well as shown by grosscomparison. In addition, control cells maintained a typically angularmorphological structure as indicating in FIG. 7A. Magnetic field-treatedcells showed significantly decreased cell count and in additiondemonstrated rounded morphology indicating cell stress, as shown in FIG.7B.

FIG. 8 provides a bar chart comparison summarizing the results oftreatments performed on two different plates with 36 wells in eachplate. Normalizing the cell counts of the control wells as 100, thetreated cells showed a reduction of approximately 31%. Althoughtreatment by magnetic fields and electrical fields (e.g., TTF therapy)are fundamentally different (e.g., using coils vs electrodes andgenerating primarily magnetic vs. electric fields), it is possible tocalculate the strength of the induced electric field from the coils usedin Experiment 1 using the equation

$E_{nc} = {\frac{r}{2}\frac{dB}{dt}}$

Using equation 1 yields a maximum inducted voltage of 2.34 V/m, or lessthan 3% of the electric field strengths reported as required forinhibitory activity in TTF therapy. Because Experiment 1 indicates thatMFT therapy exhibits effects on cancer cells at such a small fraction ofthe electrical field strength of TTF therapy, it enables therapieshaving significant advantages over TTF therapies, including withoutlimitation ambulatory therapies that allow patients to continue manyordinary day-to-day activities without interruption, and minimalencumbrance or burden.

Part of the advantage of MFT therapies over TTF therapies stems from thedifferent hardware configurations of the two systems. While TTFtherapies use insulated (e.g., ceramic coated) electrodes, the use ofcoils instead of electrodes in MFT therapy confers a number of benefits.Because MFT therapy coils—in contrast to the insulated electrodes of TTFtherapies—do not need to be in direct contact with the body, MFT coilscan be separated from target issue by one or more clothing layers (e.g.,a garment or undergarment). By applying magnetic fields throughclothing, MFT therapies provide increased patient comfort and a lesscumbersome patient experience.

In addition, MFT therapies can be implemented with significantly lessrisk to the patient than TTF therapies involving electrodes. The use ofcoils instead of electrodes results in only a de minimis inducedelectrical current during MFT therapies, and thus the risk of electricalshorting and consequent uncontrolled heating of patient body tissue isnegligible.

Furthermore, because MFT therapies involve coils that can be maderelatively small and with minimal current flow through the patient'sbody, systems for MFT therapies can allow long treatment periods totarget cancer and other hyperproliferating cells with littleinconvenience to the patient. These and other advantages of MFTtherapies over TTF therapies will be more fully appreciated by personsof skill in the art in view of the present disclosure.

Experiment 2

Method: Balb/c female mice were kept in plastic cages with free accessto food and water and under standardized light/dark cycle conditions.Mice were inoculated subcutaneously with 5×10⁵ 4 T1 murine breastcarcinoma cells and one week later were randomly divided into thecontrol and therapy groups.

Mice in the therapy group were exposed to therapy on the same day asthey were randomized, which is designated as d₀. The length, width, andheight of the tumor were measured with a fine caliper twice each weekfor the study duration. The tumor volume was expressed as0.5×length×width×height of the tumor. Antitumor activity was evaluatedover the study duration, and the tumor growth inhibition ratio (IR) wascalculated at the study end date (d_(f)) using the equation

IR% = 1 − (meanRTVofdrugtreatedgroup/meanRTVofcontrolgroup) * 100,${{where}{RTV}( {{relative}{tumor}{volume}} )} = \frac{{tumor}{volume}{of}{df}}{{tumor}{volume}{on}d0}$

Results: After the model development, 10 mice were divided randomly intocontrol and therapy groups (n=5 for each arm). Mice in the therapy groupwere continuously exposed to an alternating polarity magnetic fieldhaving a frequency of 26 kHz (±1 khz) and a magnetic field strength ofapproximately 1 mT for 32 days. FIG. 9 shows the measured tumor volumeover the study duration for the control and therapy groups. Theinhibition ratio (IR) in the therapy group was 25.9%. FIG. 9 suggeststhat the cancer-inhibiting effects of MFT therapy may be measurable asearly as 4 days after the start of the therapy, and that the effects ofthe therapy become more significant over time, as illustrated by thedifference in tumor volume at the end of the study (day 31).

Experiment 3

Method: As in Experiment 2, balb/c female mice kept in plastic cageswith free access to food and water under standardized light/dark cycleconditions were subcutaneously inoculated with 5×10⁵ 4T1 murine breastcarcinoma cells, then randomly divided into control and therapy groupsone week later. Mice in the therapy treatment groups were exposed totherapy the same day as randomization (d₀), and tumor volume andinhibition ratio (IR) were calculated as in Experiment 2.

Results: After the model development, the mice were randomly dividedinto control and 3 therapy groups (n=6 in each of the control and threetherapy groups, 24 mice total). Therapy was provided as an alternatingpolarity magnetic field having a field strength of 0.8-1 mT (all therapygroups) and frequencies of 26 kHz (±1 khz), 51 khz (±1 khz) and 97 khz(±1 khz), respectively, for therapy groups 1, 2 and 3. Therapy wasprovided continuously for 28 days, at which time the animals weresacrificed. The tumor was measured twice every week and the tumor volumewas estimated form these measurements. FIG. 12 shows the tumor growthacross all 4 groups.

FIG. 12 suggests that, at least for the 4T1 murine breast carcinomacells under study, there appears to be a frequency-dependent response,with greatest efficacy at approximately 50 kHz. Without being bound bytheory, it is believed that therapies for various cancer cell types maybe characterized by a frequency distribution that describes an optimaltherapy response. It is also hypothesized that an optimum frequency orfrequency distribution may be experimentally determinable for differenttypes of cancer cells, and that therapy may be provided as a single(optimum) frequency that provides the maximum inhibition ratio, or as afrequency distribution including the optimum frequency. Alternatively,alternating polarity magnetic fields at multiple individual frequencies,or multiple overlapping or non-overlapping frequency distributionsvarying in a random, non-random, or time-dependent distribution (e.g., aGaussian distribution) may be used to treat cancers of various types.

The MFT therapies of Experiments 2 and 3 suggest that MFTT does notinduce toxicity and is tolerable to the patient. A weight loss during atherapy study is often considered as a sign of therapy toxicity. Miceweight was typically measured twice a week throughout Experiments 2 and3, and there was no significant difference in mice weight between thetherapy and control arms at therapy end (d_(f)).

Based on the results of Experiments 2 and 3, in one embodiment theinvention comprises a method for treating cancer cells by applying to atarget body area or body region an alternating polarity magnetic fieldhaving a field strength of from 0.05-5 mT and a frequency within therange of 1 kHz-100 kHz, where the magnetic field selectively affects thecancer cells to achieve at least one of damaging the cancer cells,inhibiting their growth, reducing tumor size, inhibiting angiogenesis,eliciting an immune response to the cancer cells, increasing tumorimmunogenicity, decreasing immunosuppressive activity of the cancercells, recruiting one of antigen-presenting cells and immune effectorcells to the tumor microenvironment, or preventing metastasis of thecancer cells. In one embodiment, the therapy leaves non-cancer cellssubstantially unharmed. In various embodiments, the method may compriseapplying to cancer cells in a target body area or region an alternatingpolarity magnetic field having a frequency within a frequency rangeselected from 0.2-400 kHz, 0.5-300 kHz, 1-200 kHz, 5-150 kHz, 10-100kHz, and 25-100 kHz.

In one embodiment, the AP magnetic fields may be applied to the body ofthe patient using one or more coils, the operation of which may becontrolled by a controller that controls the parameters of the magneticfield therapy, which may include frequency, field strength, duty cycle,etc. The controller may also control the operation of various sensorssuch as body parameter sensors (e.g., temperature sensors, neuralactivity sensors, etc.) and sensors adapted to detect one or moreeffects of the MFT therapy, such as ultrasound sensors to detect tumorsize, e.g., ultrasound waves delivered to the patient using one or moreultrasound generating elements such as a piezoelectric ultrasoundelement.

FIG. 10 illustrates a system according to one embodiment of theinvention using ultrasound to image the cancer cells in the target bodyarea simultaneously or sequentially with the delivery of a magneticfield tumor therapy (MFTT). Certain components of the system are similarto like components in the system of FIG. 1. For example, coils 1020,magnetic field generator 1010, magnetic field controller 103 (includingtiming control module 1012, frequency control module 1014, and magneticfield strength control module 1016), interface 1040, and power supply1050 provide similar functions to those of coils 120, magnetic fieldgenerator 110, magnetic field controller 130, timing control module 112,frequency control module 114, magnetic field strength control module116, interface 1040, and power supply 1050 of FIG. 1. For brevity,discussion of those elements of FIG. 10 is simplified herein.

In larger mammalian subjects, including human patients, in oneembodiment the invention comprises delivering an MFT therapy systemcomprising at least one body-worn electromagnetic coil 1120 and one ormore ultrasound elements 1060 coupled to the patient (e.g., in anarticle of clothing and/or an ultrasound sensor retaining element), andperiodically imaging the tumor using the ultrasound elements 1060 (whichmay comprise, e.g., ultrasound delivery elements and ultrasoundsensors). In one embodiment, the system may comprise an ultrasoundgenerator 1065 coupled to the ultrasound elements (e.g., piezoelectricprobes and sensors to detect reflected ultrasound energy from bodytissue) and to a controller 1070 having software to analyze theultrasound data and/or images and using the images to interrupt,restart, or adjust therapy, thereby providing a closed-loop therapy.

In the embodiment of FIG. 10, ultrasound controller 1070 includes atiming control module 1072 for controlling the timing of ultrasoundimages (e.g., obtaining images at a frame rate of 1-500 frames persecond for a defined time periods and/or timepoints (such as once every10 minutes, 5 images every 30 minutes, etc.), an ultrasound probecontrol module 1074 for controlling the application of ultrasound energyto the target body area and the detection of reflected ultrasound energyfrom the target via ultrasound elements 1060, and an ultrasound imagegeneration and analysis module 1076 for processing the ultrasound energyreflected from the patient's body to produce ultrasound images of thecancer cells (e.g., a tumor).

Although depicted as separate elements in FIG. 10, it will beappreciated by persons of skill in the art in view of the presentdisclosure that ultrasound controller 1070 and its substructures may becombined with those of magnetic field controller 1030 in a singlecontroller. In an alternative embodiment, separate controller elementsmay be provided for some or each of the substructures of the ultrasoundcontroller 1070 and magnetic field controller 1030.

The MFT therapy system of FIG. 10 further comprises a power supply 1080and one or more interfaces 1090 for a user (e.g., a patient and/orcaregiver), although it will be appreciated that power supply 1080 maybe combined with power supply 1050 into a single power supply (which maycomprise one or more of a battery or standard interface to an AC systemsuch as a wall socket). Likewise, interfaces 1090 and 1040 may becombined into a single interface for a particular user (e.g., patient,caregiver) that provides information on both the MFT therapy and theultrasound portion of the system (e.g., providing ultrasound images fordisplay to the patient or caregiver).

In one embodiment, the system of FIG. 10 may provide a closed-looptherapy in which the magnetic field controller 1030 uses ultrasound data(e.g., ultrasound images from image generation/analysis module 1076) toautomatically change a parameter of the MFT therapy (e.g., the magneticfield strength, the magnetic field frequency, duty cycle, on time, offtime, etc.). In another embodiment, the magnetic field controller mayuse the ultrasound data to take additional actions, such as tocommunicate a message to the patient or a caregiver, to recommend achange in a therapy parameter of the MFTT or a drug therapy, to turn theMFTT on or off, or to turn an adjunctive therapy (e.g., a TTF therapy ora nanoparticle hyperthermia therapy) on or off, etc.

In one embodiment, ultrasound images of cancer cells and/or a tumors inthe target body area may be automatically captured (e.g., usingultrasound elements 1060, ultrasound generator 1065, and ultrasoundimage generation and analysis module 1076) and transmitted (e.g.,automatically via a body-worn computing device coupled to a wireless orcloud-based network) to one or both of the patient and a healthcareprovider, who may analyze the images and transmit instructions to abody-worn therapy system to change one or more therapy parameters.

In one embodiment, the invention comprises delivering an MFTT using asystem comprising at least one body-worn electromagnetic coil and one ormore heating or cooling elements to deliver a magnetic field therapy toa target body area or region of the patient simultaneously orsequentially with a hyperthermia or hyperthermia therapy to heat or coolcancer cells (e.g., a tumor). Hyperthermia therapy, in which tumors areheated, has been shown to inhibit tumors. Without being bound by theory,it is hypothesized that providing both MFTT and hyperthermia therapy mayresult in more efficacious therapies for treating cancer cells. In oneembodiment, one or more ultrasound delivery elements 1060 (e.g.,piezoelectric elements, not shown) may be used as heating elements toprovide the hyperthermia elements. In a particular embodiment, theultrasound elements may be used for both imaging and for providinghyperthermia elements. In other embodiments, separate ultrasoundelements by be provided for imaging and for hyperthermia therapy.

In a still further embodiment, the invention comprises providing an MFTTto a patient and using nanoparticles to apply a hyperthermia therapy toa target body area or region comprising cancer cells. In a particularembodiment, nanoparticles may be delivered to a tumor, and heated by theMFTT system by applying one or more of an alternating polarity magneticfield, ultrasound energy, or another heat source (not shown) to the nanoparticles. The alternating polarity magnetic field used to heat thenanoparticles may have a field strength and frequency as previouslydescribed, or may have different field strength and frequency parametersthan those used to provide the MFT therapy.

Without being bound by theory, it is believed that MFTT operates in atleast one mode of action by favorably altering the tumormicroenvironment (TME) and can work synergistically with otheranti-cancer therapies, including without limitation immunotherapies.Cell phenotyping of the TME in some experiments (described hereinafter)support this hypothesis.

Tumor microenvironment or TME refers to the area (which may moreaccurately comprise a volume of tissue in the patient's body)surrounding the cancer cells/tumor that encompasses surrounding bloodvessels, fibroblasts, immune cells, signaling molecules, theextracellular matrix, resident and infiltrating host cells, secretedfactors, proteins, tumor vasculature and lymphatics, pericytes andsometimes adipocytes. The TME is a complex ecosystem where subtleinteractions profoundly impact tumor progression by influencingprocesses that lead to tumor eradication, increased metastasis, or theestablishment of dormant micrometastases. The tumor microenvironment canalso shape therapeutic responses and resistance, justifying the recentimpetus to target components of the tumor microenvironment, which isbest exemplified by the success of immunotherapies in the clinic.Because cancer cells may be present in the body outside of a tumor, themore generic term “cancer microenvironment” may also be used to clarifythat methods and systems of the present invention may be used tomodulate one or more aspects of the environment surrounding cancercells. However, the terms are interchangeable, and “cancermicroenvironment,” “CME,” “tumor microenvironment,” and “TME” as usedherein are each intended to refer to the area as described above,regardless of whether the cancer cells are part of a tumor.

Despite the fact that immunotherapies have revolutionized cancer care inthe last ten years, most patients nevertheless do not respond to them.Research efforts are currently underway to develop therapies that canfavorably alter the TME to produce and improve patient outcomes, eitherwhen used as a monotherapy or when used in conjunction with other cancertherapies (including immunotherapies).

Immune cells in the TME are fundamental determinants of the invasive andmetastatic activity of the cancer cells, and of the tumor's fate. Adominant anti-tumor immune cell is the CD8+ T lymphocyte, which canrecognize tumor cells in an antigen-specific manner and secretecytotoxic molecules to kill them directly. Studies have shown thatcancer patients with high CD8+ levels have significantly betterrecurrence-free survival and overall survival rates. However, beforethey are able to perform their cytotoxic functions to destroy cancercells, CD8+ T cells must be primed and “educated” by antigen presentingcells (APCs), which are dendritic cells.

In contrast to the anti-tumor effects of the CD8+ T cells,myeloid-derived suppressor cells (MDSCs) in the TME promote cancer cellgrowth. MDSCs are a heterogeneous population of various types ofimmature myeloid cells that recent studies have shown to cause immunesuppression and cancer progression through a variety of mechanisms.Studies have established that elevated MDSC levels in cancer patientsare associated with shorter overall patient survival and poordisease-free survival and/or recurrence-free survival.

While cells such as the CD8+ T cells and MDSCs show a consistentanti-cancer or pro-cancer activity, other immune cells demonstrateplasticity in the MTE, and are capable of either tumor-promoting ortumor-inhibiting activity, depending upon other factors in the TME. Forexample, while some macrophages (M1) primarily produce pro-inflammatorycytokines that potentiate the anti-tumor immune response, others (M2)can promote immunosuppression, again depending upon the TME.

Analyses of the TME in retrospective cohort studies across differenttumors has established a clear correlation between the density ofinfiltrating immune cells and the patient's clinical outcome. Ingeneral, these studies have established that the presence of the maincellular players orchestrating the cytotoxic anti-tumor immune response(e.g., cytotoxic CD8+ T cells, mature activated dendritic cells (DCs),and tumor-infiltrating lymphocytes (TILs) are associated with a goodclinical outcome in the vast majority of tumor types. In contrast, highdensities of M2 macrophages and MDSCs are associated with poorprognosis.

MFT In Vitro Testing

To test the effects of MFT therapy, in vitro tests were conducted on avariety of cancer cell lines by exposing the cancer cells to magneticfields at defined parameters. The growth of the cancer cells exposed toMFT was compared to cell growth of non-exposed control cancer cells. Theresults indicate that MFT therapy was able to disrupt cell growth inmultiple cell lines, but also that the outcome depends on exposurefrequency and field strength. In particular, exposure above a certainfrequency of approximately 500 kHz does not result in a statisticallysignificant reduction in the rate of cancer cell growth.

FIG. 11 summarizes the results of a number of experiments treating theMB231 cell line of triple negative breast cancer (TNBC), a highlyaggressive cancer, and for the B16F10 melanoma cell line. TNBC cells donot have estrogen or progesterone receptors and produce little HER2protein. Consequently, treatment options for these cancers are limited,primarily to chemotherapies. Moreover, though TNBC may respond tochemotherapy initially, recurrences of TNBC after such response is morefrequent that in other breast cancers.

Each row in the table of FIG. 11 shows the results of a series ofexperiments in which a number of wells having the cell line were exposedto MFT therapy at a particular frequency and field strength. In oneexperiment, 20 wells on 96 well plates of the MB231 TNBC cells wereexposed for 4 days to magnetic fields at a frequency of 525 kHz and 78μT (0.078 mT). At the end of the test, MFT therapy-exposed cells showedsimilar cell growth as control cells. In another experiment, 20 wells on96 well plates of the MB231 TNBC cells were exposed for 4 days tomagnetic fields at a frequency of 745 kHz and 36 μT (0.036 mT). At theend of the test, MFT therapy-treated cells showed similar cell growth ascontrol cells. Both lines 1 and 2 suggest that MFT at frequenciesexceeding approximately 500 kHz might not be effective.

In another experiment, 20 wells in 96 well plates of the MB231 TNBCcells were exposed for 4 days to AP magnetic fields at a frequency of 20kHz and 275 μT (0.275 mT). As indicated in Line 3 of Table 11, theMFT-exposed cells showed a statistically significant reduction in cellgrowth compared to the control group. This corresponded to a 15%reduction of the MFT-exposed cells vs. controls, with a statisticallysignificant p-value of less than 0.005. In another experiment, B16F10melanoma cells in 36 wells in a 96 well plate were exposed for 1 day toAP magnetic fields at a frequency of 150 kHz at a field strength of 800μT (0.8 mT). Line 4 of Table 11 indicates that the MFT-exposed cellsshowed a statistically significant reduction in cell growth compared tothe control group. This corresponded to a 31% reduction of theMFT-exposed cells vs. controls, with a statistically significant p-valueof less than 0.0001.

MFT Therapy Preclinical Studies

MFT therapy has shown promising results in initial preclinical studieson two different animal models covering breast (4T1) and colon cancers(CT26), including inhibiting tumor growth rate (FIGS. 12 and 13) andreducing tumor metastasis to distant organs (FIG. 14). These studiesalso indicate that using MFT therapy in conjunction with animmunotherapy (checkpoint inhibitor anti-PD1 drug) further improvestherapy efficacy.

FIG. 12 is a graph showing the increase in tumor volume over a 30-dayperiod for breast cancer cells (4T1 cell line) in an animal modelinvolving in which control and MFT therapy-treated animals were testedas described in connection with Experiments 2 and 3 above. Treatmentanimals were exposed continuously for 30 days to an AP magnetic field at26 kHz, 50 kHz, or 100 kHz frequencies and a field strength of 1 mT.Control animals were not exposed to magnetic field therapy. As shown inthe graph of FIG. 12, animals treated with MFT at frequencies of 26 and50 kHz showed a diminished growth in tumor volume at sacrifice at 30days, while animals treated at a frequency of 100 kHz showed an increasein tumor growth relative to control. This study suggests that theeffects of MFT are dependent upon frequency.

FIG. 13 is a graph showing the increase in tumor volume over a 30-dayperiod for colon cancer cells (CT6 cell line) in an animal modelcomparing the combination of MFT therapy (50 kHz, 1 mT) and a checkpointinhibitor anti-PD1 drug (an immunotherapy drug) to the checkpointinhibitor drug alone, and to isotype IgG2a and control (no exposure toMFT or any drug) animals. Balb/c mice kept in plastic cages with freeaccess to food and water under standardized light/dark cycle conditionswere subcutaneously inoculated with 2×106 CT26 cells, then randomlydivided into 4 groups one week later. The graph of FIG. 13 shows thatanimals treated with immunotherapy showed a diminished growth in tumorvolume after 30 days compared to control and isotype animals.Significantly, animals treated with the combination of MFT therapy andthe immunotherapy drug show even further diminished growth compared tothe immunotherapy drug alone, suggesting a synergistic effect of MFTtherapy and immunotherapy.

FIG. 14 is a bar graph showing relative metastasis of breast cancercells (4T1 cell line) in an animal lung model. MFT therapy (50 kHz, 1mT) and the anti-PDF checkpoint inhibitor drug were each used alone inseparate animals, and in a third cohort animals were treated both MFTtherapy and the anti-PDF checkpoint inhibitor drug. In this experiment,balb/c female mice kept in plastic cages with free access to food andwater under standardized light/dark cycle conditions were subcutaneouslyinoculated with 5×105 4T1 murine breast carcinoma cells, then randomlydivided into 4 groups one week later. The animals were sacrificed 28days after initiation of therapy and the metastatic lung metastases werevisually counted. The first bar in FIG. 14 shows the average number oflung metastasis nodules in the control group. The second bar shows thenumber of lung metastasis nodules in animals exposed to MFT therapyalone, and shows a significant reduction compared to control animals.The third bar shows that animals treated with the anti-PDF checkpointinhibitor drug alone show a decrease in metastatic lung nodules relativeto control but not as significant as MFT therapy alone. The fourth barshows that animals treated with both MFT therapy and immunotherapyexhibited a dramatic decrease in metastatic lung nodules relative tocontrol, MFT alone, and immunotherapy alone. FIG. 14 shows that MFTtherapy and immunotherapy appear to be strongly synergistic forinhibiting metastasis for at least some cancers.

MFT Therapy and TME Cell Phenotypes

Studies of the effect of MFT on TME cell phenotypes have shown that MFTtherapy favorably alters the TME by increasing the number of CD8+ Tcells (FIG. 15), and the number of dendritic cells (FIG. 16), whilereducing the number of granular MDSCs (FIG. 17).

FIG. 15 is a bar graph showing CD8+ T cells as a percentage of all cellsin the TME in a breast cancer cell (4T1 cell line) animal model.Concentrations of CD8_cells were measured using flow cytometry. Asstated earlier the CD8+ T cells exhibit an anti-cancer effect. Treatedanimals were exposed to either MFT therapy (50 kHz, 1 mT) alone; thecheckpoint inhibitor anti-PD1 drug alone; or both MFT therapy and thecheckpoint inhibitor anti-PD1 drug. The first bar shows control animalshaving a very low presence of CD8+ cells. In contrast, animals exposedto MFT therapy (50 kHz, 1 mT) showed a much higher concentration of CD8+cells, suggesting that MFT therapy can be used to modify the TME so asto inhibit tumor progression. The checkpoint inhibitor anti-PD1 drug didnot show a greater concentration of CD8+ cells relative to the control(Bar 3), and the animals treated with both MFT therapy and checkpointinhibitor anti-PD1 drug showed an intermediate concentration of CD8+cells relative to MFT-exposed animals and control animals.

FIG. 16 is a bar graph showing the relative concentration of MDSC cellsas a percentage of all cells in the TME in the same breast cancer animalmodel as FIG. 15 (4T1 cell line). MDSCs, as previously noted, correlatewith poor patient survival. As in FIG. 15, treated animals were exposedto either MFT therapy (50 kHz, 1 mT) alone; the checkpoint inhibitoranti-PD1 drug alone; or both MFT therapy and the checkpoint inhibitoranti-PD1 drug.

Control animals (Bar 1) showed, as expected, a relatively highconcentration of MDSCs, as did animals treated with the checkpointinhibitor anti-PD1 drug alone (Bar 3). Animals exposed to MFT therapy(50 kHz, 1 mT) showed a significantly diminished relative concentrationof MDSCs than control or drug-treated animals. Animals treated with bothMFT therapy and the checkpoint inhibitor anti-PD1 drug showed anintermediate concentration of MDSCs, between the MFT therapy animals andthe control or drug-treated animals. FIGS. 15 and 16 suggest that MFTshows strong enhancement of certain anti-cancer cells and/or reductionof pro-cancer cells in the TME, an effect that is somewhat reduced byco-therapy with the drug.

FIG. 17 is a bar graph showing the relative concentration of dendriticcells (DCs) as a percentage of all cells in the TME in the same breastcancer animal model as FIGS. 15 and 16 (4T1 cell line). DCs exhibit ananti-cancer/antitumor effect and correlate with improved patientsurvival. As in FIGS. 15 and 16, treated animals were exposed to eitherMFT therapy (50 kHz, 1 mT) alone; the checkpoint inhibitor anti-PD1 drugalone; or both MFT therapy and the checkpoint inhibitor anti-PD1 drug.

Control animals (Bar 1) showed a relatively low concentration ofdendritic cells. Animals treated with MFT therapy alone (Bar 2) showedan improvement in the concentration of dendritic cells relative tocontrol animals. Bar 3 shows a small increase in dendritic cellconcentration relative to MFT-treated animals in animals treated withimmunotherapy alone. Animals treated with both MFT therapy and thecheckpoint inhibitor anti-PD1 drug, on the other hand, showed a furtherincrease in the concentration of dendritic cells relative to control,MFT-treated animals, and drug-treated animals.

Results from these preclinical studies have shown that MFT therapyinhibits tumor growth and prevents metastasis. Cell phenotyping of TMEusing flow cytometry indicates that MFT therapy works by favorablyaltering the TME, in particular by increasing the CD8+ and dendriticcells and decreasing the granular MDSC cells.

In various embodiments, the present invention relates to the subjectmatter of the following numbered paragraphs.

101. A method of treating cancer cells in a target body area of apatient, comprising:

using an alternating polarity (AP) magnetic field generator comprising:

-   -   an alternating polarity (AP) magnetic field generator;    -   one or more AP electromagnetic coils coupled to the AP magnetic        field generator, wherein the one or more AP electromagnetic        coils are energized by an electrical signal from the AP magnetic        field generator to generate an AP magnetic field having at least        a frequency and a field strength; and    -   a controller to control at least one of the frequency and the        field strength of the AP magnetic field generated by the one or        more AP electromagnetic coils; coupling the one or more AP        electromagnetic coils to the target body area;        generating an AP magnetic field having a frequency of 0.5-500        kHz and a field strength of 0.1-500 kHz and a field strength of        0.2-5 mT using the one or more AP electromagnetic coils; and

applying the generated AP magnetic field to the target body area usingthe one or more AP electromagnetic coils, wherein the AP magnetic fieldselectively affects the cancer cells to achieve at least one of

-   -   increasing the number of CD8+ lymphocytes in the TME;    -   increasing the ratio of CD8+ to total lymphocytes in the TME;    -   increasing the number of CD4+ lymphocytes;    -   increasing the ratio of CD4+ to total lymphocytes in the TME;    -   increasing the number of tumor infiltrating lymphocytes (TILs)        in the TME;    -   increasing the number of antigen presenting cells (APCs) in the        TME;    -   increasing the concentration of tumor-suppressive cytokines in        the TME;    -   decreasing the concentration of tumor-promoting cytokines in the        TME;    -   increasing the number of M1 macrophages in the TME;    -   decreasing the number of M2 macrophages in the TME;    -   decreasing one of the number or concentration of myloid-derived        suppressor cells (MDSCs) in the TME;    -   increasing one of the number or concentration of natural killer        (NK) cells in the TME.

102. The method of numbered paragraph 101, wherein generating an APmagnetic field comprises generating an AP magnetic field having afrequency within a frequency range selected from 0.2-400 kHz, 0.5-300kHz, 1-200 kHz, 5-150 kHz, 10-100 kHz, and 25-100 kHz; and a fieldstrength within a field strength range selected from of 0.2-5 mT,0.2-4.0 mT, 0.4-3.0 mT, 0.5-2.0 mT, and 0.1-1.6 mT.

104. The method of numbered paragraph 101, wherein the AP magnetic fieldselectively affects the cancer cells to achieve at least one of damagingthe cancer cells, inhibiting the growth of the cancer cells, reducingtumor size, inhibiting angiogenesis, eliciting an immune response to thecancer cells, increasing tumor immunogenicity, decreasingimmunosuppressive activity of the cancer cells, recruiting one ofantigen-presenting cells and immune effector cells to the tumormicroenvironment, or preventing metastasis of the cancer cells, whileleaving non-cancer cells substantially unharmed.

105. The method of numbered paragraph 101, further comprising: shieldingat least one non-target body area from exposure to the AP magnetic fieldduring the step of applying the generated AP magnetic field to thetarget body area.

106. The method of numbered paragraph 101, wherein coupling the one ormore AP electromagnetic coils to the target body area comprises using aretaining element to maintain the AP electromagnetic field generator ina desired position proximate to the target body area, and wherein theretaining element is selected from a garment and a bandage.

107. The method of numbered paragraph 106, wherein the cancer cells arebrain cancer cells selected from astrocytomas, glioblastoma multiforme,meningioma, and pituitary tumors, and the retaining element is a headcovering selected from a hat, a helmet, and a garment head covering.

201. A method of treating cancer cells in a target body area of apatient, comprising:

providing at least one electromagnetic coil;

providing a controller coupled to the at least one electromagnetic coil;

coupling the at least one electromagnetic coil to the target body area;

applying to the target body area an alternating polarity (AP) magneticfield having a frequency of 0.5-500 kHz and a field strength of 0.05-5mT, wherein the AP magnetic field is generated by the at least oneelectromagnetic coil under the control of the controller, and the APmagnetic field selectively affects the cancer cells to achieve at leastone of damaging the cancer cells, inhibiting the growth of the cancercells, reducing tumor size, inhibiting angiogenesis, eliciting an immuneresponse to the cancer cells, increasing tumor immunogenicity,decreasing immunosuppressive activity of the cancer cells, recruitingone of antigen-presenting cells and immune effector cells to the tumormicroenvironment, or preventing metastasis of the cancer cells, whileleaving non-cancer cells substantially unharmed.

202. The method of numbered paragraph 201, wherein applying an APmagnetic field comprises applying an AP magnetic field having afrequency of 1-400 kHz and a field strength of 0.2-2 mT.

203. The method of numbered paragraph 201, wherein applying an APmagnetic field comprises applying an AP magnetic field having afrequency of 10-100 kHz and a field strength of 0.5-1.5 mT.

204. The method of numbered paragraph 201, wherein applying an APmagnetic field comprises applying the AP electrical field to the targetbody area according to at least one of a treatment duty cycle and afield strength duty cycle.

205. The method of numbered paragraph 204, wherein the treatment dutycycle comprises alternating periods of an on-time in which the APmagnetic field is applied to the target tissue, and an off-time in whichthe AP magnetic field is not applied to the target tissue.

206. The method of numbered paragraph 204, wherein the field strengthduty cycle comprises alternating periods in which the AP magnetic fieldis applied to the target tissue for a first time period at a first fieldstrength followed by a second time period at a second field strength.

207. The method of numbered paragraph 201, wherein the AP magnetic fieldcomprises a bimodal magnetic field frequency distribution comprising afirst variable AP magnetic field that varies the magnetic fieldfrequency between a first lower limit and a first upper limit and asecond variable AP magnetic field that varies the magnetic fieldfrequency between a second lower limit and a second upper limit.

208. The method of numbered paragraph 201, wherein the AP magnetic fieldcomprises at least one of a variable frequency and a variable fieldstrength.

209. The method of numbered paragraph 1, further comprisingadministering to the patient at least one additional anti-cancer therapyselected from an anti-cancer drug, a radiation therapy, and TTF therapy.

210. The method of numbered paragraph 209, wherein administering a TTFtherapy comprises applying at least one AC electrical field to thetarget tissue, wherein the AC electrical field comprises a frequency of50-500 kHz and an electric field strength of about 10-1000 V/m.

301. A system for treating cancer cells in a target body area of apatient comprising:

at least one electromagnetic coil coupled to a target body area; anda controller for controlling the at least one electromagnetic coil togenerate and apply to the target body area an AP magnetic field having afrequency of 0.5-500 kHz and a field strength of 0.05-5 mT, wherein theAP magnetic field selectively affects the cancer cells to achieve atleast one of damaging the cancer cells, inhibiting the growth of thecancer cells, reducing tumor size, inhibiting angiogenesis, eliciting animmune response to the cancer cells, increasing tumor immunogenicity,decreasing immunosuppressive activity of the cancer cells, recruitingone of antigen-presenting cells and immune effector cells to the tumormicroenvironment, or preventing metastasis of the cancer cells, whileleaving non-cancer cells substantially unharmed.

302. The system of numbered paragraph 301, wherein the cancer cells areone of brain cancer cells, breast cancer cells, lung cancer cells, lungcarcinoid tumor cells, thymic cancer cells, tracheal cancer cells,pancreatic cancer cells, liver cancer cells, stomach cancer cells,kidney cancer cells, ovarian cancer cells, colon cancer cells, rectalcancer cells, prostate cancer cells, throat cancer cells, thyroid cancercells, mouth cancer cells, nose cancer cells, and salivary gland cancercells.

303. The system of numbered paragraph 302 wherein the at least oneelectromagnetic coil is coupled to the target body area by a retainingelement during the application of the AP magnetic field to the targetbody area.

304. The system of numbered paragraph 303, wherein the cancer cells arebreast cancer cells, and the retaining element is a wearable garmentselected from a bra, a shirt, and a vest.

305. The system of numbered paragraph 303, wherein the cancer cells areselected from lung cancer, lung carcinoid tumors, thymic malignancies,tracheal tumors, pancreatic cancer, liver cancer, stomach cancer, kidneycancer, ovarian cancer, colon cancer and rectal cancer, and theretaining element is a wearable garment selected from a bra, a shirt, avest, and a jacket.

306. The system of numbered paragraph 303, wherein the cancer cells arelower-body cancer cells selected from prostate cancer cells, ovariancancer cells, colon cancer cells, and rectal cancer cells, and theretaining element is an undergarment.

307. The system of numbered paragraph 303, wherein the cancer cells arebrain cancer cells and the retaining element is a head covering selectedfrom a hat, a helmet, and a garment head covering.

308. The system of numbered paragraph 301 wherein the at least oneelectromagnetic coil is coupled to the target body area by a retainingelement during the application of the AP magnetic field to the targetbody area.

309. The system of numbered paragraph 308 wherein the retaining elementis selected from a bra, a shirt, a vest, a jacket, an undergarment, anda bandage.

310. The system of numbered paragraph 301, wherein the at least oneelectromagnetic coil comprises a plurality of electromagnetic coilscoupled to the target body area to obtain a desired magnetic fielddistribution in the target body area.

311. The system of numbered paragraph 301, further comprising:

an electromagnetic shield for shielding at least one non-target bodyarea of the patient's body from exposure to the AP magnetic field.

401. A system for treating cancer cells in a target area of a patient'sbody comprising:

at least one electromagnetic coil coupled to a target body area; and

a controller for controlling the at least one electromagnetic coil togenerate and apply to the target body area an alternating polarity (AP)magnetic field having a frequency of 0.1-500 kHz and a field strength of0.05-5 mT, wherein the AP magnetic field selectively affects the cancercells to achieve at least one of damaging the cancer cells, inhibitingthe growth of the cancer cells, reducing tumor size, inhibitingangiogenesis, eliciting an immune response to the cancer cells,increasing tumor immunogenicity, decreasing immunosuppressive activityof the cancer cells, recruiting one of antigen-presenting cells andimmune effector cells to the tumor microenvironment (TME), or preventingmetastasis of the cancer cells, while leaving non-cancer cellssubstantially unharmed.

402. The system of numbered paragraph 401, further comprising:

a power supply for supplying power to said electromagnetic coil.

501. A system for treating cancer cells in a target body area of apatient comprising:

at least one electromagnetic coil coupled to a target body area;

a power supply for supplying power to said electromagnetic coil; and

a controller for controlling the at least one electromagnetic coil andpower supply to generate and apply to the target body area an APmagnetic field having a frequency of 0.1-500 kHz and a field strength of0.1-5 mT, wherein the AP magnetic field modifies the cancermicroenvironment (TME) by at least one of:

-   -   increasing the number of CD8+ lymphocytes in the TME;    -   increasing the ratio of CD8+ to total lymphocytes in the TME;    -   increasing the number of CD4+ lymphocytes;    -   increasing the ratio of CD4+ to total lymphocytes in the TME;    -   increasing the number of tumor infiltrating lymphocytes (TILs)        in the TME;    -   increasing the number of antigen presenting cells (APCs) in the        TME;    -   increasing the concentration of tumor-suppressive cytokines in        the TME;    -   decreasing the concentration of tumor-promoting cytokines in the        TME;    -   increasing the number of M1 macrophages in the TME;    -   decreasing the number of M2 macrophages in the TME;    -   decreasing one of the number or concentration of myloid-derived        suppressor cells (MDSCs) in the TME; and        increasing one of the number or concentration of natural killer        (NK) cells in the TME.

502. The system of numbered paragraph 501, wherein the AP magnetic fieldachieves at least one of damaging the cancer cells, inhibiting thegrowth of the cancer cells, reducing tumor size, preventing metastasisof the cancer cells, and inhibiting angiogenesis for the cancer cells,while leaving non-cancer cells substantially unharmed.

503. The system of numbered paragraph 501, wherein the AP magnetic fieldfurther affects at least one additional modification of the TME selectedfrom modulating the blood vessels surrounding the cancer cells,modulating the presence of fibroblasts proximate to the cancer cells,modulating immune cell signaling molecules proximate to the cancercells, modulating the extracellular matrix surrounding the cancer cells,modulating resident host cells, modulating infiltrating host cells,modulating secreted factors proximate to the cancer cells, modulatingthe proteins surrounding the cancer cells, modulating the concentrationof pericycles proximate to the cancer cells, and modulating theadipocytes proximate to the cancer cells.

504 The system of numbered paragraph 501, wherein the at least oneelectromagnetic coil is maintained in close proximity to the target bodyarea by a retaining element during the application of the AP magneticfield to the target body area, and wherein the retaining elementselected from a garment and a bandage.

505. The system of numbered paragraph 504, wherein the at least oneelectromagnetic coil, the retaining element, the power supply, and thecontroller are each wearable by the user, and wherein the systemcomprises an ambulatory treatment system capable of providing treatingthe cancer cells while the patient is non-stationary.

506. The system of numbered paragraph 501, wherein the at least oneelectromagnetic coil comprises a plurality of electromagnetic coils, andthe retaining element is selected from a hat, a cap, a bra, a shirt, anda vest, and is adapted to maintain the plurality of electromagneticcoils in a desired position relative to the target body area.

507. The system of numbered paragraph 501, wherein the controllercomprises a timing control module to control the one or moreelectromagnetic coil to perform at least one of:

applying the AP magnetic field continuously to the target body area fora first treatment period;applying the AP magnetic field intermittently for a second treatmentperiod in alternating on time periods in which the AP magnetic field isapplied to the target body area, followed by off time periods in whichthe AP magnetic field is not applied to the target body area; applyingthe AP magnetic field intermittently for one or more circadian treatmentperiods based on circadian rhythms of the patient; andapplying the AP magnetic field intermittently for one or more thirdtreatment periods at defined times of day.

508. The system of numbered paragraph 501, wherein the controllercomprises:

a frequency control module to control the one or more electromagneticcoil to perform at least one of:

applying an AP magnetic field having a single frequency of 1-500 kHz tothe target body area;

applying an AP magnetic field having a frequency of 1-500 kHz thatvaries in a defined pattern;

applying an AP magnetic field having multiple simultaneous frequenciesof 1-100 kHz; and

applying an AP magnetic field having a bimodal magnetic field frequencydistribution comprising a first variable AP magnetic field distributionthat varies the magnetic field frequency between a first lower limit anda first upper limit and a second variable AP magnetic field distributionthat varies the magnetic field frequency between a second lower limitand a second upper limit.

509. The system of numbered paragraph 508, wherein the frequency controlmodule further controls the one or more electromagnetic coil to apply anAP magnetic field having at least one of:

a frequency of 1-500 kHz that varies randomly;

a frequency that varies in a Gaussian distribution in one or more rangeswithin the range of 1-500 kHz;

a frequency that varies in a non-Gaussian distribution in one or moreranges within the range of 1-500 kHz.

510. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 0.2-400 kHz and a field strength of 0.2-4 mT.

511. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 0.5-300 kHz and a field strength of 0.4-3 mT.

512. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 1.0-200 kHz and a field strength of 0.5-2 mT.

513. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 5.0-150 kHz and a field strength of 0.1-1.6 mT.

514. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 10.0-100 kHz and a field strength of 0.1-5 mT.

515. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field having afrequency of 25.0-100 kHz and a field strength of 0.1-5 mT.

516. The system of numbered paragraph 501, wherein the controllercontrols the at least one electromagnetic coil and power supply togenerate and apply to the target body area an AP magnetic field comprisea series of pulse bursts, where each pulse in the pulse burst occurs ata pulse frequency of 0.01-1000 Hz and has a pulse duration of 0.1-5000msec, and wherein each pulse in the pulse burse comprises a frequency of0.1-500 kHz and a field strength of 0.1-5 mT.

601. A system for treating cancer cells in a target body area of apatient comprising:

at least one electromagnetic coil coupled to a target body area;

a power supply for supplying power to said electromagnetic coil; and

a controller for controlling the at least one electromagnetic coil andpower supply to generate and apply to the target body area an APmagnetic field having a frequency of 0.1-500 kHz and a field strength of0.1-5 mT, wherein the AP magnetic field achieves at least one ofdamaging the cancer cells, inhibiting the growth of the cancer cells,reducing tumor size, preventing metastasis of the cancer cells, andinhibiting angiogenesis for the cancer cells, while leaving non-cancercells substantially unharmed.

701. A system for treating cancer cells in a target body area of apatient comprising:

at least one electromagnetic coil coupled to a target body area;

a power supply for supplying power to said electromagnetic coil; and

a controller for controlling the at least one electromagnetic coil andpower supply to generate and apply to the target body area an APmagnetic field having a frequency of 0.1-500 kHz and a field strength of0.1-5 mT, wherein the AP magnetic field modifies the cancermicroenvironment (TME) by at least one of:

modulating the blood vessels surrounding the cancer cells;

modulating the presence of fibroblasts proximate to the cancer cells;

modulating immune cell signaling molecules proximate to the cancercells;

modulating the extracellular matrix surrounding the cancer cells;

modulating resident host cells;

modulating infiltrating host cells;

modulating secreted factors proximate to the cancer cells;

modulating the proteins surrounding the cancer cells;

modulating the presence of pericycles proximate to the cancer cells; and

modulating the presence of adipocytes proximate to the cancer cells.

The particular embodiments disclosed above are illustrative only, as theinvention may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Embodiments of the present invention disclosed andclaimed herein may be made and executed without undue experimentationwith the benefit of the present disclosure. While the invention has beendescribed in terms of particular embodiments, it will be apparent tothose of skill in the art that variations may be applied to systems andapparatus described herein without departing from the concept, spiritand scope of the invention. Examples are all intended to benon-limiting. It is therefore evident that the particular embodimentsdisclosed above may be altered or modified and all such variations areconsidered within the scope and spirit of the invention, which arelimited only by the scope of the claims.

What is claimed is:
 1. A system for treating cancer cells in a targetbody area of a patient comprising: an alternating polarity (AP) magneticfield generator; one or more AP electromagnetic coils coupled to the APmagnetic field generator and adapted to be coupled to the target bodyarea, wherein the one or more AP electromagnetic coils are energized byan electrical signal from the AP magnetic field generator to generate anAP magnetic field having a first frequency of 0.1-500 kHz and a fieldstrength of 0.2-5 mT; a controller to control the AP magnetic fieldgenerator, the one or more AP electromagnetic coils, and at least one ofthe first frequency and the first field strength; wherein the APmagnetic field modifies the cancer microenvironment (TME) by at leastone of: increasing the number of CD8+ lymphocytes in the TME; increasingthe ratio of CD8+ to total lymphocytes in the TME; increasing the numberof CD4+ lymphocytes; increasing the ratio of CD4+ to total lymphocytesin the TME; increasing the number of tumor infiltrating lymphocytes(TILs) in the TME; increasing the number of antigen presenting cells(APCs) in the TME; increasing the concentration of tumor-suppressivecytokines in the TME; decreasing the concentration of tumor-promotingcytokines in the TME; increasing the number of M1 macrophages in theTME; decreasing the number of M2 macrophages in the TME; decreasing oneof the number or concentration of myloid-derived suppressor cells(MDSCs) in the TME; and increasing one of the number or concentration ofnatural killer (NK) cells in the TME.
 2. The system of claim 1, furthercomprising: a power supply for supplying power to said electromagneticcoil.
 3. The system of claim 1, wherein the AP magnetic field achievesat least one of damaging the cancer cells, inhibiting the growth of thecancer cells, reducing tumor size, preventing metastasis of the cancercells, and inhibiting angiogenesis for the cancer cells, while leavingnon-cancer cells substantially unharmed.
 4. The system of claim 1,wherein the AP magnetic field further modifies the TME by at least oneof: modulating the blood vessels surrounding the cancer cells;modulating the presence of fibroblasts proximate to the cancer cells;modulating immune cell signaling molecules proximate to the cancercells; modulating the extracellular matrix surrounding the cancer cells;modulating resident host cells; modulating infiltrating host cells;modulating secreted factors proximate to the cancer cells; modulatingthe proteins surrounding the cancer cells; modulating the concentrationof pericycles proximate to the cancer cells; and modulating adipocytesproximate to the cancer cells.
 5. The system of claim 1, furthercomprising: a retaining element for retaining the one or more APelectromagnetic coils in a desired position during the application ofthe AP magnetic field to the target body area, and wherein the retainingelement selected from a garment and a bandage.
 6. The system of claim 5,wherein the one or more AP electromagnetic coils, the retaining element,and the controller are each wearable by the user, and wherein the systemcomprises an ambulatory treatment system capable of treating the cancercells while the patient is non-stationary.
 7. The system of claim 6,wherein the one or more AP electromagnetic coils comprises a pluralityof AP electromagnetic coils, and the retaining element is selected froma hat, a cap, a bra, a shirt, and a vest, and is adapted to maintain theplurality of electromagnetic coils in a desired position relative to thetarget body area.
 8. The system of claim 1, wherein the controllercomprises: a timing control module to perform at least one of: applyingthe AP magnetic field continuously to the target body area for a firsttreatment period; applying the AP magnetic field intermittently for asecond treatment period in alternating on time periods in which the APmagnetic field is applied to the target body area, followed by off timeperiods in which the AP magnetic field is not applied to the target bodyarea; applying the AP magnetic field intermittently for one or morecircadian treatment periods based on circadian rhythms of the patient;and applying the AP magnetic field intermittently for one or more thirdtreatment periods at defined times of day.
 9. The system of claim 1,wherein the controller comprises: a frequency control module to performat least one of: applying an AP magnetic field having a single frequencyof 1-500 kHz to the target body area; applying an AP magnetic fieldhaving a frequency of 1-500 kHz that varies in a defined pattern;applying an AP magnetic field having multiple simultaneous frequenciesof 1-500 kHz; and applying an AP magnetic field having a bimodalmagnetic field frequency distribution comprising a first variable APmagnetic field distribution that varies the magnetic field frequencybetween a first lower limit and a first upper limit and a secondvariable AP magnetic field distribution that varies the magnetic fieldfrequency between a second lower limit and a second upper limit.
 10. Thesystem of claim 9 wherein the frequency control module further controlsthe AP magnetic field generator and the one or more AP electromagneticcoils to apply an AP magnetic field having at least one of: a frequencyof 1-500 kHz that varies randomly; a frequency that varies in a Gaussiandistribution in one or more ranges within the range of 1-500 kHz; afrequency that varies in a non-Gaussian distribution in one or moreranges within the range of 1-500 kHz.
 11. The system of claim 1, whereinthe controller controls the AP magnetic field generator and the one ormore AP electromagnetic coils to generate and apply to the target bodyarea an AP magnetic field having a frequency of 0.2-400 kHz and a fieldstrength of 0.2-4 mT.
 12. The system of claim 1, wherein the controllercontrols the AP magnetic field generator and the one or more APelectromagnetic coils to generate and apply to the target body area anAP magnetic field having a frequency of 0.5-300 kHz and a field strengthof 0.4-3 mT.
 13. The system of claim 1, wherein the controller controlsthe AP magnetic field generator and the one or more AP electromagneticcoils to generate and apply to the target body area an AP magnetic fieldhaving a frequency of 1.0-200 kHz and a field strength of 0.5-2 mT. 14.The system of claim 1, wherein the controller controls the AP magneticfield generator and the one or more AP electromagnetic coils to generateand apply to the target body area an AP magnetic field having afrequency of 5.0-150 kHz and a field strength of 0.1-1.6 mT.
 15. Thesystem of claim 1, wherein the controller controls the AP magnetic fieldgenerator and the one or more AP electromagnetic coils to generate andapply to the target body area an AP magnetic field having a frequency of10.0-100 kHz and a field strength of 0.1-5 mT.
 16. The system of claim1, further comprising an immunotherapy drug, wherein the immunotherapydrug is administered to the patient one of before, during, or aftercoupling the one or more AP electromagnetic coils to the target bodyarea, wherein the controller controls the AP magnetic field generatorbased at least in part on the dosage of the immunotherapy drug, andwherein the AP magnetic field modifies the cancer microenvironment (TME)by increasing the efficacy of the immunotherapy drug.
 17. The system ofclaim 1, wherein the controller controls the AP magnetic field generatorand the one or more AP electromagnetic coils to generate and apply tothe target body area an AP magnetic field comprising a series of pulsebursts, where each pulse in the pulse burst occurs comprises apredefined number of AP magnetic waveforms having a frequency of 0.1-500kHz and a field strength of 0.1-5 mT, and the pulses in the pulse burstare applied at a pulse frequency of 0.01-1000 Hz and a pulse duration of0.1-5000 msec.
 18. The system of claim 1, wherein the AP magnetic fieldmodifies the cancer microenvironment (TME) by at least one of:increasing the number of CD8+ lymphocytes in the TME; increasing theratio of CD8+ to total lymphocytes in the TME; decreasing the number ofmyloid-derived suppressor cells (MDSCs) in the TME modulating the bloodvessels surrounding the cancer cells; decreasing the concentration ofmyloid-derived suppressor cells (MDSCs) in the TME modulating the bloodvessels surrounding the cancer cells; increasing the number of tumorinfiltrating lymphocytes (TILs) in the TME; increasing the number of M1macrophages in the TME; and decreasing the number of M2 macrophages inthe TME.
 19. The system of claim wherein the AP magnetic field modifiesthe cancer microenvironment (TME) of a brain cancer, wherein the braincancer comprises one of cancerous brain tissue and a cancer metastasizedto the brain from another region of the patient's body.
 20. A system fortreating cancer cells in a target body area of a patient comprising: analternating polarity (AP) magnetic field generator; one or more APelectromagnetic coils coupled to the AP magnetic field generator andadapted to be coupled to the target body area, wherein the one or moreAP electromagnetic coils are energized by an electrical signal from theAP magnetic field generator to generate an AP magnetic field having afirst frequency of 0.1-500 kHz and a field strength of 0.2-5 mT; acontroller for controlling the AP magnetic field generator, the one ormore AP electromagnetic coils, and at least one of the first frequencyand the first field strength; wherein the AP magnetic field modifies thecancer microenvironment (TME) by at least one of: modulating the bloodvessels surrounding the cancer cells; modulating the presence offibroblasts proximate to the cancer cells; modulating immune cellsignaling molecules proximate to the cancer cells; modulating theextracellular matrix surrounding the cancer cells; modulating residenthost cells; modulating infiltrating host cells; modulating secretedfactors proximate to the cancer cells; modulating the proteinssurrounding the cancer cells; modulating the presence of pericyclesproximate to the cancer cells; and modulating the presence of adipocytesproximate to the cancer cells.